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192 results on '"Immunologie et Neurogénétique Expérimentales et Moléculaires ( INEM )"'

1. Expression Profile of ERK5 and PKM2 Kinases in Neuroinflammatory Diseases. (NEUROKINASE)

Author: Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM)
Published: 2023

2. Stress-Induced Depressive Behaviors Require a Functional NLRP3 Inflammasome

Author: Jesús Ruiz-Cabello, Mario D. Cordero, Cristina Ulecia-Morón, Nieves Casas-Barquero, Angel M. Carrión, François Ghiringhelli, Pedro Bullón, Elísabet Alcocer-Gómez, José Antonio Sánchez-Alcázar, Lionel Apetoh, Tatyana Rybkina, Fabiola Marín-Aguilar, Bernhard Ryffel, Universidad Pablo de Olavide [Sevilla] (UPO), University of Sevilla, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Departamento de Fisica [UC Santiago], Pontificia Universidad Católica de Chile (UC), Universidad Pablo de Olavide, University Seville, Immunologie et Neurogénétique Expérimentales et Moléculaires ( INEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Departamento de Fisica [Santiago], Pontificia Universidad Católica de Chile, Junta de Andalucía, Dirección General de Investigación Científica y Técnica, DGICT (España), and Fundación Ramón Areces
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Neurology, Inflammasomes, Mediator, Neuroscience (miscellaneous), Prefrontal Cortex, Activation, Stress, Hippocampus, Inflammasome, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, NLR Family, Pyrin Domain-Containing 3 Protein, Major Depression, Hippocampal Neurogenesis, Animals, Medicine, Interpersonal Relations, Depression (differential diagnoses), Neuroinflammation, Mice, Knockout, integumentary system, Microglia, Depression, business.industry, Neurogenesis, Brain, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Inflammasome complex, Neuroscience, Stress, Psychological, 030217 neurology & neurosurgery, Pathway, medicine.drug
Abstract: et al., Depression is a major public health concern in modern society, yet little is known about the molecular link between this condition and neuroinflammation. The inflammasome complex was recently shown to be implicated in depression. The present study shows the implication of NLRP3 inflammasome in animal model of stress-induced depression. Accordingly, we show here that in the absence of a NLRP3 inflammasome, prolonged stress does not provoke depressive behaviors or microglial activation in mice or dampen hippocampal neurogenesis. Indeed, NLRP3 deletion or inhibition of microglial activation impairs the stress-induced alterations associated with depression. According to these findings in animal model, the inflammasome could be a target for new therapeutic interventions to prevent depression in patients., This work has been supported by Grupo de Investigacion Junta de Andalucia CTS113, Consejería de Salud of the Junta de Andalucia (PI0036-2014), Fundación Ramón Areces, and the Departamento Gobernamental de Investigaciones Científicas y Tecnológicas (DGICYT: BFU2008-01,552 and BFU2011-27,207).
Published: 2015
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3. Protein kinase C θ controls type 2 innate lymphoid cell and TH2 responses to house dust mite allergen

Author: Marc Le Bert, Nathalie Rouxel, Quentin Marquant, Pauline Chenuet, Fabrice Trovero, Chloé Beuraud, Dieudonnée Togbe, Bernhard Ryffel, Louis Fauconnier, Tiffany Marchiol, Laurent Mascarell, Fahima Madouri, Margaux Gallerand, Vincent Lombardi, Valérie F. J. Quesniaux, François Erard, Aurélie Ledru, Lionel Apetoh, Immunologie et Neurogénétique Expérimentales et Moléculaires ( INEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Stallergenes Greer (France, Antony), Artimmune, privé, Eco-Anthropologie et Ethnobiologie ( EAE ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Muséum National d'Histoire Naturelle ( MNHN ), Equipe CD4DNA (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institute of Immunology and Infectious Disease and Molecular Medicine, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Eco-Anthropologie et Ethnobiologie (EAE), Muséum national d'Histoire naturelle (MNHN)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement
Subjects: 0301 basic medicine, Adoptive cell transfer, medicine.medical_treatment, Immunology, interferon regulatory factor 4, innate lymphoid cells, Biology, House dust mite, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, Protein kinase C, Innate lymphoid cell, FOXP3, protein kinase Cθ, Dendritic cell, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Eosinophil, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Cytokine, [ SDV.SP ] Life Sciences [q-bio]/Pharmaceutical sciences, nuclear factor of activated T cells, eosinophils, Cell activation, allergic asthma, 030215 immunology
Abstract: Background Protein kinase C (PKC) θ, a serine/threonine kinase, is involved in T H 2 cell activation and proliferation. Type 2 innate lymphoid cells (ILC2s) resemble T H 2 cells and produce the T H 2 cytokines IL-5 and IL-13 but lack antigen-specific receptors. The mechanism by which PKC-θ drives innate immune cells to instruct T H 2 responses in patients with allergic lung inflammation remains unknown. Objectives We hypothesized that PKC-θ contributes to ILC2 activation and might be necessary for ILC2s to instruct the T H 2 response. Methods PRKCQ gene expression was assessed in innate lymphoid cell subsets purified from human PBMCs and mouse lung ILC2s. ILC2 activation and eosinophil recruitment, T H 2-related cytokine and chemokine production, lung histopathology, interferon regulatory factor 4 (IRF4) mRNA expression, and nuclear factor of activated T cells (NFAT1) protein expression were determined. Adoptive transfer of ILC2s from wild-type mice was performed in wild-type and PKC-θ–deficient (PKC-θ −/− ) mice. Results Here we report that PKC-θ is expressed in both human and mouse ILC2s. Mice lacking PKC-θ had reduced ILC2 numbers, T H 2 cell numbers and activation, airway hyperresponsiveness, and expression of the transcription factors IRF4 and NFAT1. Importantly, adoptive transfer of ILC2s restored eosinophil influx and IL-4, IL-5 and IL-13 production in lung tissue, as well as T H 2 cell activation. The pharmacologic PKC-θ inhibitor (Compound 20) administered during allergen challenge reduced ILC2 numbers and activation, as well as airway inflammation and IRF4 and NFAT1 expression. Conclusions Therefore our findings identify PKC-θ as a critical factor for ILC2 activation that contributes to T H 2 cell differentiation, which is associated with IRF4 and NFAT1 expression in allergic lung inflammation.
Published: 2017
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4. Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance

Author: Valentina Sica, Frank Madeo, Norma Bloy, Maria Chiara Maiuri, Erika Vacchelli, David Enot, Fernando Aranda, Laura Senovilla, Jonathan Pol, Sarah Levesque, Nicolas Jacquelot, Elisa E. Baracco, Laurence Zitvogel, Lionel Apetoh, Guillermo Mariño, Takahiro Yamazaki, Francesca Castoldi, Aitziber Buqué, Josef M. Penninger, Bernhard Ryffel, Simonetta Falzoni, Beth Levine, Verena Sigl, Sylvère Durand, Sylvie Lachkar, Francesco Di Virgilio, Alexis Chery, Guido Kroemer, Shuan Rao, Federico Pietrocola, Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche des Cordeliers (CRC), Université Paris-Sud - Paris 11 (UP11), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Cancérologie Intégratives (CRC - Inserm U1138), Group of Immune receptors of the Innate and Adaptive System, Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), RENARD (TGE Réseau National de RPE interdisciplinaire - 3443 ), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Université de Strasbourg (UNISTRA)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Université de Lille-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), LAboratoire de Recherche Historique Rhône-Alpes - UMR5190 (LARHRA), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service de pneumologie, oncologie thoracique et soins intensifs respiratoires [Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institute of Molecular Biosciences, Karl-Franzens University Graz, (IMB), Karl-Franzens-Universität Graz, Apoptose, cancer et immunité (U848), Institute of Molecular Biotechnology, Austrian Academy of Sciences (OeAW), Karolinska University Hospital [Stockholm], Service de biologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Lille-Sorbonne Université (SU)-Aix Marseille Université (AMU)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie et Cancérologie Intégratives ( CRC - Inserm U1138 ), Mathématiques Appliquées à Paris 5 ( MAP5 - UMR 8145 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National des Sciences Mathématiques et de leurs Interactions-Centre National de la Recherche Scientifique ( CNRS ), RENARD ( TGE Réseau National de RPE interdisciplinaire ), FR-CNRS 3443, LAboratoire de Recherche Historique Rhône-Alpes - UMR5190 ( LARHRA ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -Université Jean Moulin - Lyon III-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Hôpital Charles Nicolle [Rouen]-CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Immunologie et Neurogénétique Expérimentales et Moléculaires ( INEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Institute of Molecular Biosciences, Karl-Franzens University Graz, ( IMB ), Apoptose, cancer et immunité ( U848 ), Austrian Academy of Sciences ( OeAW ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Apoptose, cancer et immunité ( Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 ), Institut Gustave Roussy ( IGR ) -Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre National de la Recherche Scientifique ( CNRS ) -Université Jean Moulin - Lyon III ( UJML ) -Université Lumière - Lyon 2 ( UL2 ) -École normale supérieure - Lyon ( ENS Lyon ) -Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Grenoble Alpes ( UGA ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Hôpital Charles Nicolle [Rouen]-CHU Rouen, Pietrocola, Federico, Pol, Jonathan, Vacchelli, Erika, Rao, Shuan, Enot, David P, Baracco, Elisa E, Levesque, Sarah, Castoldi, Francesca, Jacquelot, Nicola, Yamazaki, Takahiro, Senovilla, Laura, Marino, Guillermo, Aranda, Fernando, Durand, Sylvère, Sica, Valentina, Chery, Alexi, Lachkar, Sylvie, Sigl, Verena, Bloy, Norma, Buque, Aitziber, Falzoni, Simonetta, Ryffel, Bernhard, Apetoh, Lionel, Di Virgilio, Francesco, Madeo, Frank, Maiuri, MARIA CHIARA, Zitvogel, Laurence, Levine, Beth, Penninger, Josef M, and Kroemer, Guido
Subjects: 0301 basic medicine, Cancer Research, ATP citrate lyase, Spermidine, Bariatric Surgery, immunosurveillance, T-Lymphocytes, Regulatory, Autophagy-Related Protein 5, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, chemistry.chemical_compound, Mice, regulatory T cell, Citrates, 3. Good health, Immunogenic Cell-Death, Immunosurveillance, medicine.anatomical_structure, Oncology, Biochemistry, Differentiation, embryonic structures, Immunogenic cell death, In-Vivo, Human, Regulatory T cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Dietary Restriction, NO, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Monitoring, Immunologic, In vivo, Cell Line, Tumor, medicine, Autophagy, Animals, Humans, cancer, Chemotherapy, Breast-Cancer, Caloric Restriction, chemotherapy, immunosurveillance, regulatory T cell, Animal, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, regulatory T&nbsp, fungi, Neoplasms, Experimental, cell, Methotrexate, 030104 developmental biology, chemistry, Acetylation, Mutation, Cancer research, Citrate, Neoplasm Transplantation
Abstract: International audience; Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.
Published: 2016
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5. Infection-Mediated Priming of Phagocytes Protects against Lethal Secondary Aspergillus fumigatus Challenge

Author: Oumaïma Ibrahim-Granet, Amélie Savers, Bernhard Ryffel, Marianna Parlato, Gérard Eberl, Grégory Jouvion, Jean-Marc Cavaillon, Orhan Rasid, Matthias Brock, Cytokines et Inflammation, Institut Pasteur [Paris], School of Life Sciences, University of Nottingham, UK ( UON ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Histopathologie humaine et Modèles animaux, Immunologie et Neurogénétique Expérimentales et Moléculaires ( INEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Développement des Tissus Lymphoïdes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), This work was supported by funding from Institut Pasteur PTR 468 to OIG and AS, and the Transregio 124 'FungiNet' project A3 to AS and MB., University of Nottingham, UK (UON), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris] (IP), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and BENEDIC, Bénédicte
Subjects: MESH : Bone Marrow, MESH : Spores, Fungal, medicine.medical_treatment, MESH : Cytokines, MESH: Flow Cytometry, Pathology and Laboratory Medicine, Aspergillosis, MESH: Phagocytes, Aspergillus fumigatus, Animal Cells, MESH : Aspergillosis, MESH: Animals, lcsh:Science, skin and connective tissue diseases, Lung, Disease Resistance, Fungal Pathogens, Phagocytes, Innate Immune System, MESH: Cytokines, Flow Cytometry, 3. Good health, [SDV] Life Sciences [q-bio], Aspergillus, Blood, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Aspergillus Fumigatus, Medical Microbiology, Spectrophotometry, Cytokines, MESH: Bone Marrow, Cytophotometry, Cellular Types, MESH : Receptors, Interleukin-8B, Immune Cells, Phagocytosis, Immunology, 030106 microbiology, Microbiology, 03 medical and health sciences, Microbial Pathogens, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Blood Cells, [ SDV ] Life Sciences [q-bio], Macrophages, lcsh:R, MESH: Host-Pathogen Interactions, Organisms, Biology and Life Sciences, Molecular Development, medicine.disease, Molds (Fungi), Mice, Inbred C57BL, 030104 developmental biology, lcsh:Q, Developmental Biology, 0301 basic medicine, Chemokine, Neutrophils, [SDV]Life Sciences [q-bio], lcsh:Medicine, MESH: Mice, Knockout, Receptors, Interleukin-8B, White Blood Cells, Spectrum Analysis Techniques, Bone Marrow, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, Immune Physiology, Medicine and Health Sciences, MESH : Lectins, C-Type, CXC chemokine receptors, MESH : Host-Pathogen Interactions, Mice, Knockout, Mice, Inbred BALB C, Multidisciplinary, Bone Marrow/immunology/metabolism, biology, MESH: Receptors, Interleukin-8B, Hematology, Spores, Fungal, MESH: Chemokines, Body Fluids, Cytokine, Cell Processes, Host-Pathogen Interactions, MESH : Phagocytes, Aspergillus fumigatus/immunology, Chemokines, Pathogens, Anatomy, MESH: Aspergillus fumigatus, Research Article, MESH : Flow Cytometry, MESH : Lung, MESH: Mice, Inbred BALB C, MESH: Disease Resistance, Mycology, MESH : Mice, Inbred C57BL, Research and Analysis Methods, Immune system, MESH: Mice, Inbred C57BL, MESH: Spores, Fungal, medicine, MESH : Disease Resistance, Animals, Lectins, C-Type, MESH: Lung, MESH : Chemokines, MESH: Aspergillosis, MESH : Mice, Inbred BALB C, Innate immune system, Fungi, Cell Biology, Aspergillosis/immunology/microbiology, biology.organism_classification, Immune System, MESH : Aspergillus fumigatus, physiology, biology.protein, MESH : Mice, Knockout, MESH : Animals, MESH: Lectins, C-Type
Abstract: International audience; Phagocytes restrict the germination of Aspergillus fumigatus conidia and prevent the establishment of invasive pulmonary aspergillosis in immunecompetent mice. Here we report that immunecompetent mice recovering from a primary A. fumigatus challenge are protected against a secondary lethal challenge. Using RAGγc knock-out mice we show that this protection is independent of T, B and NK cells. In protected mice, lung phagocytes are recruited more rapidly and are more efficient in conidial phagocytosis and killing. Protection was also associated with an enhanced expression of CXCR2 and Dectin-1 on bone marrow phagocytes. We also show that protective lung cytokine and chemokine responses are induced more rapidly and with enhanced dynamics in protected mice. Our findings support the hypothesis that following a first encounter with a non-lethal dose of A. fumigatus conidia, the innate immune system is primed and can mediate protection against a secondary lethal infection.
Published: 2016
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6. The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients

Author: Marie-Ange Delrue, Nathalie Golovkine, Annick Toutain, Marie-Jose Gregoire, Christel Thauvin-Robinet, Nicolas Gruchy, Cédric Le Caignec, Emilie Landais, Bruno Delobel, Olivier Tassy, Pascal Sabouraud, Laurence Taine, Caroline Fiquet, Nathalie Leporrier, Agathe Paubel, Dominique Gaillard, Philippe Jonveaux, Nathalie Bednarek, Jacques Motte, Bruno Leheup, Olivier Brichet, Albert David, Didier Lacombe, Martine Doco-Fenzy, Stéphanie Arpin, Mylène Beri, Sylvain Briault, Monique Mozelle-Nivoix, Camille Leroy, Francine Mugneret, Service de Génétique, Centre Hospitalier Universitaire de Reims ( CHU Reims ) -Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne ( URCA ) -Université de Reims Champagne-Ardenne ( URCA ), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ), Centre de génétique et Centre de référence maladies rares et anomalies du développement et syndromes malformatifs du Centre Est, Département de Génétique et Procréation UF-Hôpital Couple Enfant de Grenoble-CHU Grenoble, Plateforme Régionale de Biologie Innovante, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Immunologie et Neurogénétique Expérimentales et Moléculaires ( INEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Génétique Clinique [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Laboratoire de cytogénétique et génétique moléculaire [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Université de Lorraine ( UL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Maladies Rares - Génétique et Métabolisme ( MRGM ), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Service de génétique [Tours], Hôpital Bretonneau-CHRU Tours, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, American Memorial Hospital (Reims), Service de génétique [Reims], Service de psychothérapie de l’enfant et l’adolescent [CHU Reims], Université de Reims Champagne-Ardenne ( URCA ), Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Centre Hospitalier Universitaire de Reims (CHU Reims), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Maladies Rares - Génétique et Métabolisme (MRGM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Université de Reims Champagne-Ardenne (URCA), UL, NGERE, Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: Adult, Male, Candidate gene, Adolescent, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Chromosome Disorders, Locus (genetics), Biology, Fibrous Dysplasia, Polyostotic, Bioinformatics, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Humans, Child, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, KIF1A, Behavior, Comparative Genomic Hybridization, 0303 health sciences, [ SDV ] Life Sciences [q-bio], medicine.diagnostic_test, Brachydactyly, Chromosome Mapping, Overweight, Subtelomere, medicine.disease, [SDV] Life Sciences [q-bio], Child, Preschool, Chromosomes, Human, Pair 2, Autism, Female, Chromosome Deletion, 030217 neurology & neurosurgery, Comparative genomic hybridization, Fluorescence in situ hybridization
Abstract: International audience; The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable ‘2q37-deletion syndrome’ or Albright’s hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8 Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype–phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1.
Published: 2012
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7. Haslea ostrearia Pigment Marennine Affects Key Actors of Neuroinflammation and Decreases Cell Migration in Murine Neuroglial Cell Model

Author: Sarah Méresse, Hélène Gateau, Tessa Tirnan, Vanessa Larrigaldie, Nathalie Casse, Pamela Pasetto, Jean-Luc Mouget, Stéphane Mortaud, Mostefa Fodil, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), BIOlogie des populations, Stress, Santé, Environnement (BIOSSE), Université Catholique de l'Ouest (UCO), Institut des Molécules et Matériaux du Mans (IMMM), Le Mans Université (UM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), FEDER N°EX016008 TARGET-EX, GHaNA (The Genus Haslea, New marine resources for blue biotechnology and Aquaculture) 734708/GHANA/H2020-MSCA-RISE-2016, and European Project: EX016008,TARGET-EX
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Organic Chemistry, General Medicine, migration, biomolecules, Catalysis, diatoms, neuroinflammation, Computer Science Applications, Inorganic Chemistry, Haslea ostrearia, marennine, neuroglial cells, immunostimulation, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract: International audience; Haslea ostrearia, a cosmopolitan marine pennate diatom, produces a characteristic blue pigment called marennine that causes the greening of filter-feeding organisms, such as oysters. Previous studies evidenced various biological activities of purified marennine extract, such as antibacterial, antioxidant and antiproliferative effects. These effects could be beneficial to human health. However, the specific biological activity of marennine remains to be characterized, especially regarding primary cultures of mammals. In the present study, we aimed to determine in vitro the effects of a purified extract of marennine on neuroinflammatory and cell migratory processes. These effects were assessed at non-cytotoxic concentrations of 10 and 50μg/mL on primary cultures of neuroglial cells. Marennine strongly interacts with neuroinflammatory processes in the immunocompetent cells of the central nervous system, represented by astrocytes and microglial cells. An anti-migratory activity based on a neurospheres migration assay has also been observed. These results encourage further study of Haslea blue pigment effects, particularly the identification of molecular and cellular targets affected by marennine, and strengthen previous studies suggesting that marennine has bioactivities which could be beneficial for human health applications.
Published: 2023
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8. Prolonged response after TPO-RA discontinuation in primary ITP: results of a prospective multicenter study

Author: Stephanie Guillet, Etienne Crickx, Imane Azzaoui, pascal chappert, Emmanuelle Boutin, Jean-François Viallard, Etienne Riviere, Delphine Gobert, Lionel Galicier, Marion Malphettes, Stéphane Cheze, Francois Lefrere, Sylvain Audia, Bernard Bonnotte, Olivier Lambotte, Nicolas Noel, Olivier Fain, Guillaume Moulis, Mohamed Hamidou, Mathieu Gerfaud-Valentin, Jean-Pierre Marolleau, Louis Terriou, Nihal Martis, Anne-Sophie Morin, Antoinette Perlat, Thomas Le Gallou, Frédérique Roy-Peaud, Ailsa Robbins, Jean-Christophe Lega, Mathieu Puyade, Thibault Comont, Nicolas Limal, Laetitia Languille, Anissa Zarour, Marine Luka, Mickaël Mathieu Ménager, Thibaut Belmondo, Sophie Hue, Florence Canoui-Poitrine, Marc Michel, Bertrand Godeau, Matthieu Mahevas, Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), CHU Henri Mondor [Créteil], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Necker - Enfants Malades [AP-HP], Service de médecine interne et immunologie clinique (SOC 1) [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de Médecine Interne - Immunologie Clinique [AP-HP Bicêtre], Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hospices Civils de Lyon (HCL), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Immunology, Cell Biology, Hematology, Biochemistry, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Sustained response off-treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in ITP. This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response on TPO-RAs. The primary endpoint was the proportion of patients achieving SROT (platelet count > 30x109/L and no bleeding) at W24 with no other ITP-specific medications. Secondary endpoints included the proportion of sustained complete response off-treatment (SCROT, platelet count > 100x109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with median (IQR) age 58.5 years (41-73.5); 30/48 (63%) had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27/48 (56.2%, 95% CI, 41.2-70.5) achieved SROT; 15/48 (31.3%; 95% CI, 18.9-44.5) achieved SCROT at W24, and 25/48 (52.1%; 95% CI, 37.2-66.7) achieved respectively SROT and 14/48 (29.2%; 95% CI, 17.2-42.3) SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients re-challenged with TPO-RA, 11/12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA-seq revealed enrichment of a "TNFα signaling via NF-κB" signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based of progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. Clinical trial number: NCT03119974
Published: 2023
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9. Annual nationwide analysis of costs and post-operative outcomes after radical prostatectomy according to the surgical approach (open, laparoscopic, and robotic)

Author: Guilhem Roubaud, Eric Barret, Gilles Créhange, Mathieu Gauthé, Laurent Brureau, Charles-Edouard Lequeu, Romain Mathieu, Alain Ruffion, Jean-Baptiste Beauval, Morgan Rouprêt, Gaëlle Fromont, Gaelle Fiard, Annabelle Grabia, Guillaume Ploussard, Charles Dariane, Paul Sargos, Raphaële Renard-Penna, Clinique La Croix du Sud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mutualiste de Montsouris (IMM), CHU Pointe-à-Pitre/Abymes [Guadeloupe], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut Curie [Paris], Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Equipe 5 : METHODS - Méthodes de l’évaluation thérapeutique des maladies chroniques (CRESS - U1153), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Bergonié [Bordeaux], UNICANCER, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and Centre pour l'innovation en cancérologie de Lyon (CICLY)
Subjects: Male, medicine.medical_specialty, Cost, [SDV]Life Sciences [q-bio], Urology, medicine.medical_treatment, 030232 urology & nephrology, law.invention, 03 medical and health sciences, Indirect costs, 0302 clinical medicine, Robotic Surgical Procedures, law, Humans, Medicine, Post operative, Laparoscopy, Prostatectomy, Prostate cancer, Surgical approach, medicine.diagnostic_test, Volume, business.industry, Robotics, Radical prostatectomy, Intensive care unit, Treatment Outcome, Robotic systems, Cost driver, 030220 oncology & carcinogenesis, Emergency medicine, business, Complication, Readmission
Abstract: International audience; Objective Annual countrywide data are scarce when comparing surgical approaches in terms of hospital stay outcomes and costs for radical prostatectomy (RP). We aimed to assess the impact of surgical approach on post-operative outcomes and costs after RP by comparing open (ORP), laparoscopic (LRP), and robot-assisted (RARP) RP in the French healthcare system. Patients and methods Data from all patients undergoing RP in France in 2020 were extracted from the central database of the national healthcare system. Primary endpoints were length of hospital stay (LOS including intensive care unit (ICU) stay if present), complications (estimated by severity index), hospital readmission rates (at 30 and 90 days), and direct costs of initial stay. Results and limitations A total of 19,018 RPs were performed consisting in ORP in 21.1%, LRP in 27.6%, and RARP in 51.3% of cases. RARP was associated with higher center volume (p < 0.001), lower complication rates (p < 0.001), shorter LOS (p < 0.001), and lower readmission rates (p = 0.004). RARP was associated with reduced direct stay costs (2286 euros) compared with ORP (4298 euros) and LRP (3101 euros). The main cost driver was length of stay. The main limitations were the lack of mid-term data, readmission details, and cost variations due to surgery system. Conclusions This nationwide analysis demonstrates the benefits of RARP in terms of post-operative short-term outcomes. Higher costs related to the robotic system appear to be balanced by patient care improvements and reduced direct costs due to shorter LOS.
Published: 2021
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10. Synthesis of Novel 3’,3’‐cyclic Dinucleotide Analogues Targeting STING Protein

Author: Jérémy Magand, Vincent Roy, Hervé Meudal, Stéphanie Rose, Valérie Quesniaux, Dominika Chalupska, Luigi A. Agrofoglio, Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Czech Academy of Sciences [Prague] (CAS), Region Centre-Val de Loire (EURO-FéRI EX010381and EURO-FéRI EX010351), FEDER TARGET-Ex EX016008)as well as by GAVO projet (MERSI-CNRS), ICOA comes from CHemBio (FEDER-FSE 2014-2020-EX003677), Techsab (FEDER-FSE 2014-2020-EX011313), RTR Motivhealth (2019-00131403), ANR-11-LABX-0029,SYNORG,Synthèse Organique : des molécules au vivant(2011), and ANR-11-LABX-0018,IRON,Radiopharmaceutiques Innovants en Oncologie et Neurologie(2011)
Subjects: [SDV]Life Sciences [q-bio], Organic Chemistry, [CHIM]Chemical Sciences
Abstract: International audience; The Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferons in response to sensing viral or bacterial cytosolic DNA. Cyclic dinucleotides (CDNs) are known to activate STING. Here, we describe the synthesis and biological evaluation of two new 3’,3’-CDN, in which the internucleotide linkages were replaced, respectively, by a 1,2,3-triazole moiety (as more stable isosteres of phosphate linkers) and an unsaturated carbon chain (as flexibility can led to crucial binding affinity and specificity). Thus, CuAAC and macrocyclization by RCM are the two key steps
Published: 2022
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11. FMR protein: Evidence of an emerging role in retinal aging?

Author: M. Ardourel, I. Ranchon-Cole, A. Pâris, C. Felgerolle, N. Acar, F. Lesne, S. Briault, O. Perche, Université d'Orléans (UO), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Université Clermont Auvergne (UCA), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital La Source [Orléans] (HLSO), The research was supported by CHR of Orleans, CNRS of Orleans, University of Orleans and regional Centre-Val de Loire grant (FRAX-SENS, 2017-2020).Corresponding author: Genetic Department, Regional Hospital, 14 avenue de l’hôpital, F-45071, Orléans. E-mail address: olivier.perche@chr-orleans.fr (O. Perche)., and Julien, Sabine
Subjects: Adult, Aging, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Vision, Infant, Retina, Sensory Systems, Contrast Sensitivity, Mice, Fragile X Mental Retardation Protein, Cellular and Molecular Neuroscience, Ophthalmology, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Fmrp Vision Electroretinography Age-related Aging, Retinal Cone Photoreceptor Cells, Electroretinography, Humans, Animals, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Age-related, Fmrp, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Short communication 7 p.; International audience; Aging is a multifactorial process that affects the entire organism by cumulative alterations. Visual function impairments that go along with aging are commonly observed, causing lower visual acuity, lower contrast sensitivity, and impaired dark adaptation. Electroretinogram analysis revealed that the amplitudes of rod- and cone-mediated responses are reduced in aged mice and humans. Reports suggested that age-related changes observed in both rod and cone photoreceptor functionality were linked to oxidative stress regulation or free radical production homeostasis. Interestingly, several recent reports linked the fragile X mental retardation protein (FMRP) cellular activity with oxidative stress regulation in several tissue including brain tissue where FMRP participates to the response to stress via protein translation in neurite or is involved in free radical production and abnormal glutathione homeostasis. Based on these recent literatures, we raised the question about the effect of FMRP absence in the aging retina of Fmr1(-/y) compared to their WT littermates. Indeed, up to now, only young or adult mice (
Published: 2022
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12. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide

Author: Christina Pfirschke, Charles O. Elson, Marion Bérard, Florent Ginhoux, Nadine Cerf-Bensussan, Mikael J. Pittet, Fabiana Saccheri, Lionel Apetoh, François Ghiringhelli, Eric Vivier, Elisabeth Chachaty, Guido Kroemer, Paul Louis Woerther, Paule Opolon, Andreas Schlitzer, Valérie Gaboriau-Routhiau, Sophie Viaud, Chantal Bizet, Bernhard Ryffel, Patricia Lepage, Gérard Eberl, Nadia Yessaad, David Enot, Camilla Engblom, Ivo G. Boneca, Grégoire Mignot, Chantal Ecobichon, Romain Daillère, Dalil Hannani, Dominique Clermont, Joël Doré, Laurence Zitvogel, Takahiro Yamazaki, Université Paris-Sud - Paris 11 (UP11), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Apoptose, cancer et immunité (U848), Harvard Medical School [Boston] (HMS), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Microbiologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Développement des Tissus Lymphoïdes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Animalerie centrale (Plate-forme), Institut Pasteur [Paris], Groupe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Collection de l'Institut Pasteur (CIP), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, U989, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR54 IRCIV, Institut de recherche intégrée en cancérologie, Laboratoire de Pathologie Expérimentale, Institut Gustave Roussy (IGR), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), University of Alabama at Birmingham [ Birmingham] (UAB), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Paris, Université Paris Descartes - Paris 5 (UPD5), Groupe Avenir [Dijon], Programme ATIP - Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National du Cancer (INCa), la Ligue contre le cancer (LIGUE labelisee), SIRIC Socrates, LABEX, PACRI Onco-Immunology, European Research Council [202283], NIH [P01DK071176], ANR-11-PHUC-0002/11-PHUC-0002,PACRI,PACRI(2011), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-11-PHUC-0002,PACRI,Alliance Parisienne des Instituts de Recherche en Cancérologie(2011), ProdInra, Archive Ouverte, Pôle hospitalier Universitaire Cancer (PHUC) - Alliance Parisienne des Instituts de Recherche en Cancérologie - - PACRI2011 - ANR-11-PHUC-0002 - PHUC - VALID, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris-Sud - Paris 11 ( UP11 ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Apoptose, cancer et immunité ( U848 ), Harvard Medical School, Center for Systems Biology, Harvard University-Massachusetts General Hospital ( MGH ), Agency for Science, Technology and Research, Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale, Biologie et Génétique de la Paroi bactérienne, Collection de l'Institut Pasteur ( CIP ), MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Institut National de la Santé et de la Recherche Médicale-Université Paris Descartes - Paris 5 ( UPD5 ), Institut Gustave Roussy ( IGR ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Immunologie et Neurogénétique Expérimentales et Moléculaires ( INEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), The University of Alabama at Birmingham [ Birmingham] ( UAB ), Apoptose, cancer et immunité ( Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 ), Institut Gustave Roussy ( IGR ) -Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and ANR-11-PHUC-0002/11-PHUC-0002,PACRI,PACRI ( 2011 )
Subjects: Adoptive cell transfer, Cyclophosphamide, medicine.drug_class, Lymphoid Tissue, Gram-positive bacteria, [SDV]Life Sciences [q-bio], Antibiotics, Antineoplastic Agents, Gut flora, Gram-Positive Bacteria, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Neoplasms, Intestine, Small, medicine, Tumor Microenvironment, Germ-Free Life, Animals, 030304 developmental biology, 0303 health sciences, Multidisciplinary, biology, [ SDV ] Life Sciences [q-bio], Microbiota, biology.organism_classification, Adoptive Transfer, Small intestine, 3. Good health, Anti-Bacterial Agents, Intestines, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Lymphatic system, 030220 oncology & carcinogenesis, Bacterial Translocation, Immunology, Cancer research, Th17 Cells, Immunologic Memory, Immunosuppressive Agents, medicine.drug
Abstract: The Microbiota Makes for Good Therapy The gut microbiota has been implicated in the development of some cancers, such as colorectal cancer, but—given the important role our intestinal habitants play in metabolism—they may also modulate the efficacy of certain cancer therapeutics. Iida et al. (p. 967 ) evaluated the impact of the microbiota on the efficacy of an immunotherapy [CpG (the cytosine, guanosine, phosphodiester link) oligonucleotides] and oxaliplatin, a platinum compound used as a chemotherapeutic. Both therapies were reduced in efficacy in tumor-bearing mice that lacked microbiota, with the microbiota important for activating the innate immune response against the tumors. Viaud et al. (p. 971 ) found a similar effect of the microbiota on tumor-bearing mice treated with cyclophosphamide, but in this case it appeared that the microbiota promoted an adaptive immune response against the tumors.
Published: 2013
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13. Serodolin, a β-arrestin–biased ligand of 5-HT 7 receptor, attenuates pain-related behaviors

Author: Chayma El Khamlichi, Flora Reverchon, Nadège Hervouet-Coste, Elodie Robin, Nicolas Chopin, Emmanuel Deau, Fahima Madouri, Cyril Guimpied, Cyril Colas, Arnaud Menuet, Asuka Inoue, Andrzej J. Bojarski, Gérald Guillaumet, Franck Suzenet, Eric Reiter, Séverine Morisset-Lopez, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Tohoku University [Sendai], Polish Academy of Sciences (PAN), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Dynamiques de populations multi-échelles pour des systèmes physiologiques (MUSCA), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), ANR-11-LABX-0029,SYNORG,Synthèse Organique : des molécules au vivant(2011), ANR-11-LABX-0018,IRON,Radiopharmaceutiques Innovants en Oncologie et Neurologie(2011), Reiter, Eric, Laboratoires d'excellence - Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used - - MAbImprove2010 - ANR-10-LABX-0053 - LABX - VALID, Synthèse Organique : des molécules au vivant - - SYNORG2011 - ANR-11-LABX-0029 - LABX - VALID, and Radiopharmaceutiques Innovants en Oncologie et Neurologie - - IRON2011 - ANR-11-LABX-0018 - LABX - VALID
Subjects: [SDV] Life Sciences [q-bio], Multidisciplinary, GPCR, biased ligands, [SDV]Life Sciences [q-bio], 5-HT7 receptor, analgesia, serotonin
Abstract: Significance Transmembrane signaling through G protein–coupled receptors (GPCRs), originally described as requiring coupling to intracellular G proteins, also uses G protein–independent pathways through β-arrestin recruitment. Biased ligands, by favoring one of the multiple bioactive conformations of GPCRs, allow selective signaling through either of these pathways. Here, we identified Serodolin as the first β-arrestin–biased agonist of the serotonin 5-HT 7 receptor. This new ligand, while acting as an inverse agonist on G s signaling, selectively induces ERK activation in a β-arrestin–dependent way. Importantly, we report that Serodolin decreases pain intensity caused by thermal, mechanical, or inflammatory stimuli. Our findings suggest that targeting the 5-HT 7 R with β-arrestin–biased ligand could be a valid alternative strategy to the use of opioids for the relief of pain.
Published: 2022
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14. NLRP6 negatively regulates type 2 immune responses in mice

Author: Pauline Chenuet, Quentin Marquant, Louis Fauconnier, Ali Youness, Manon Mellier, Tiffany Marchiol, Nathalie Rouxel, Yasmine Messaoud‐Nacer, Isabelle Maillet, Aurélie Ledru, Valérie F. J. Quesniaux, Bernhard Ryffel, William Horsnell, Frédérique Végran, Lionel Apetoh, Dieudonnée Togbe, Université d'Orléans, SCD, Artimmune SAS, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), University of Cape Town, Institute of Microbiology and Infection, University of Birmingham [Birmingham], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Orléans, 2016-00110366/European funding in Région Centre-Val de Loire, EX0057560/European funding in Région Centre-Val de Loire, Conseil Départemental 45, Le Studium, Program ARD2020 Biomédicament, and CNRS
Subjects: Inflammasomes, Immunology, NLRP6, ILC2, Th2, Mice, Th2 Cells, inflammasome, GATA3, Immunology and Allergy, Animals, Nippostrongylus brasiliensis, birch pollen, Lymphocytes, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Mice, Knockout, Interleukin-18, Pneumonia, CD4+ T cells, Immunity, Innate, Cytokines, Th17, Nippostrongylus, allergic asthma, IL-18, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology
Abstract: International audience; Background: Inflammasomes are large protein complexes that assemble in the cytosol in response to danger such as tissue damage or infection. Following activation, inflammasomes trigger cell death and the release of biologically active forms of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome is required for IL-18 secretion by intestinal epithelial cells, macrophages, and T cells, contributing to homeostasis and self-defense against pathogenic microbes. However, the involvement of NLRP6 in type 2 lung inflammation remains elusive.Methods: Wild-type (WT) and Nlrp6−/− mice were used. Birch pollen extract (BPE)-induced allergic lung inflammation, eosinophil recruitment, Th2-related cytokine and chemokine production, airway hyperresponsiveness, and lung histopathology, Th2 cell differentiation, GATA3, and Th2 cytokines expression, were determined. Nippostrongylus brasiliensis (Nb) infection, worm count in intestine, type 2 innate lymphoid cell (ILC2), and Th2 cells in lungs were evaluated.Results: We demonstrate in Nlrp6−/− mice that a mixed Th2/Th17 immune responses prevailed following birch pollen challenge with increased eosinophils, ILC2, Th2, and Th17 cell induction and reduced IL-18 production. Nippostrongylus brasiliensis infected Nlrp6−/− mice featured enhanced early expulsion of the parasite due to enhanced type 2 immune responses compared to WT hosts. In vitro, NLRP6 repressed Th2 polarization, as shown by increased Th2 cytokines and higher expression of the transcription factor GATA3 in the absence of NLRP6. Exogenous IL-18 administration partially reduced the enhanced airways inflammation in Nlrp6−/− mice.Conclusions: In summary, our data identify NLRP6 as a negative regulator of type 2 immune responses.
Published: 2022
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15. When pharmaceutical drugs become environmental pollutants: Potential neural effects and underlying mechanisms

Author: Pascal Vaudin, Corinne Augé, Nathalie Just, Sakina Mhaouty-Kodja, Stéphane Mortaud, Delphine Pillon, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: 0303 health sciences, Wastewater, Biochemistry, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Pharmaceutical Preparations, Environmental Pollutants, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Water Pollutants, Chemical, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, Environmental Monitoring, 030304 developmental biology, General Environmental Science
Abstract: Pharmaceutical drugs have become consumer products, with a daily use for some of them. The volume of production and consumption of drugs is such that they have become environmental pollutants. Their transfer to wastewater through urine, feces or rinsing in case of skin use, associated with partial elimination by wastewater treatment plants generalize pollution in the hydrosphere, including drinking water, sediments, soils, the food chain and plants. Here, we review the potential effects of environmental exposure to three classes of pharmaceutical drugs, i.e. antibiotics, antidepressants and non-steroidal anti-inflammatory drugs, on neurodevelopment. Experimental studies analyzing their underlying modes of action including those related to endocrine disruption, and molecular mechanisms including epigenetic modifications are presented. In addition, the contribution of brain imaging to the assessment of adverse effects of these three classes of pharmaceuticals is approached.
Published: 2022
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16. XLF/Cernunnos loss impairs mouse brain development by altering symmetric proliferative divisions of neural progenitors

Author: Amandine Bery, Olivier Etienne, Laura Mouton, Sofiane Mokrani, Christine Granotier-Beckers, Laurent R. Gauthier, Justyne Feat-Vetel, Thierry Kortulewski, Elodie A. Pérès, Chantal Desmaze, Philippe Lestaveal, Vilma Barroca, Antony Laugeray, Fawzi Boumezbeur, Vincent Abramovski, Stéphane Mortaud, Arnaud Menuet, Denis Le Bihan, Jean-Pierre de Villartay, François D. Boussin, Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Bureau d'analyse et de suivi des expositions professionnelles (IRSN/PSE-SANTE/SER/BASEP), Service d'études et d'expertise en radioprotection (IRSN/PSE-SANTE/SER), Institut de Radioprotection et de Sûreté Nucléaire (IRSN)-Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Segment Radiobiologie (IRBIO, CEA), EDF, ANR-11-INBS-0006,FLI,France Life Imaging(2011), ANR-10-CESA-0007,Neuropest,Xénobiotiques, perturbation endocrinienne et neurotoxicité : impact de l'exposition chronique aux pesticides sur la reproduction, le développement et le fonctionnement du système nerveux central d'un modèle mammifère.(2010), and European Project: 323267,EC:FP7:Fission,FP7-Fission-2012,RISK - IR(2012)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, General Biochemistry, Genetics and Molecular Biology
Abstract: International audience; XLF/Cernunnos is a component of the ligation complex used in classical non-homologous end-joining (cNHEJ), a major DNA double-strand break (DSB) repair pathway. We report neurodevelopmental delays and significant behavioral alterations associated with microcephaly in Xlf−/− mice. This phenotype, reminiscent of clinical and neuropathologic features in humans deficient in cNHEJ, is associated with a low level of apoptosis of neural cells and premature neurogenesis, which consists of an early shift of neural progenitors from proliferative to neurogenic divisions during brain development. We show that premature neurogenesis is related to an increase in chromatid breaks affecting mitotic spindle orientation, highlighting a direct link between asymmetric chromosome segregation and asymmetric neurogenic divisions. This study reveals thus that XLF is required for maintaining symmetric proliferative divisions of neural progenitors during brain development and shows that premature neurogenesis may play a major role in neurodevelopmental pathologies caused by NHEJ deficiency and/or genotoxic stress.
Published: 2023
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17. Analysis of mRNA vaccination-elicited RBD-specific memory B cells reveals strong but incomplete immune escape of the SARS-CoV-2 Omicron variant

Author: Aurélien Sokal, Matteo Broketa, Giovanna Barba-Spaeth, Annalisa Meola, Ignacio Fernández, Slim Fourati, Imane Azzaoui, Andrea de La Selle, Alexis Vandenberghe, Anais Roeser, Magali Bouvier-Alias, Etienne Crickx, Laetitia Languille, Marc Michel, Bertrand Godeau, Sébastien Gallien, Giovanna Melica, Yann Nguyen, Virginie Zarrouk, Florence Canoui-Poitrine, France Noizat-Pirenne, Jérôme Megret, Jean-Michel Pawlotsky, Simon Fillatreau, Etienne Simon-Lorière, Jean-Claude Weill, Claude-Agnès Reynaud, Félix A. Rey, Pierre Bruhns, Pascal Chappert, Matthieu Mahévas, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Virologie Structurale - Structural Virology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris]-Université Paris Cité (UPCité), This work was initiated by a grant from the Agence Nationale de la Recherche and the Fondation pour la Recherche Médicale (ANR and MEMO-COV-2-FRM) and funded by the Fondation Princesse Grace, an ERC Advanced Investigator Grant (B-response), and a grant from the French Ministry of Health (Soutien Exceptionnel à la Recherche Clinique 2022, CAPNET [Comité ad-hoc de pilotage national des essais thérapeutiques et autres recherches]). Assistance Publique – Hôpitaux de Paris (AP-HP, Département de la Recherche Clinique et du Développement) was the promotor and the sponsor of MEMO-COV-2. Work in the Unit of Structural Virology was funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur. A.S. was supported by a Poste d’accueil from INSERM, I.F. by a fellowship from the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), M.B. by a CIFRE fellowship from the Association Nationale de la Recherche et de la Technologie (ANRT), and A.D.L.S by a SNFMI fellowship. P.B. acknowledges funding from the French National Research Agency grant ANR-14-CE16-0011 project DROPmAbs, the Institut Carnot Pasteur Microbes et Santé (ANR 11 CARN 0017-01), the Institut Pasteur, and the Institut National de la Santé et de la Recherche Médicale (INSERM)., We thank Garnett Kelsoe for providing the human cell culture system, together with invaluable advice, A. Boucharlat and the Chemogenomic and Biological Screening Core Facility headed by F. Agou, as well as P. England and the Molecular Biophysics Core Facility at the Institut Pasteur, Paris, France for their support during the course of this work, Sébastien Storck, Lucie Da Silva, and Sandra Weller for their advice and support, the physicians, Constance Guillaud, Raphael Lepeule, Frédéric Schlemmer, Elena Fois, Henri Guillet, Nicolas De Prost, and Pascal Lim, whose patients were included in this study, and Florence Guivel-Benhassine and Olivier Schwartz from the Institut Pasteur for providing authentic SARS-CoV-2 B.1.1.529 virus., ANR-20-COVI-0072,MEMO-COV-2,Lymphocytes B et T CD4 mémoires spécifiques du virus chez les patients guéris du Covid-19(2020), ANR-14-CE16-0011,DROP-mAbs,Analyse en profondeur de répertoires d'anticorps par microfluidique en gouttelettes couplé à du séquençage haut-débit pour le diagnostic et la découverte d'anticorps thérapeutiques(2014), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)
Subjects: B cells, MBC, variants, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Omicron, SARS-CoV-2, VOC, Immunology, Vaccination, COVID-19, Antibodies, Viral, Antibodies, Neutralizing, Infectious Diseases, mRNA vaccine, germinal center, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Spike Glycoprotein, Coronavirus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, memory B cells, Immunology and Allergy, Humans, affinity, RNA, Messenger, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology
Abstract: International audience; The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals.
Published: 2022
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18. CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of TH1 and TH9 cells

Author: Benoit-Lizon, Isis, Jacquin, Elise, Rivera Vargas, Thaiz, Richard, Corentin, Roussey, Aurélie, Dal Zuffo, Ludivine, Martin, Tiffany, Melis, Andréa, Vinokurova, Daria, Shahoei, Sayyed Hamed, Baeza Garcia, Alvaro, Pignol, Cassandre, Giorgiutti, Stéphane, Carapito, Raphaël, Boidot, Romain, Végran, Frédérique, Flavell, Richard A, Ryffel, Bernhard, Nelson, Eric R, Soulas-Sprauel, Pauline, Lawrence, Toby, Apetoh, Lionel, Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Strasbourg (UNISTRA), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Yale University School of Medicine, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), King's College Hospital (KCH), ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011), ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), ANR-14-CE14-0026,Lumugene,Etude de familles multiplex de lupus pour l'identification de nouveaux gènes à fort impact phénotypique : de la découvertes des gènes à leurs fonctions(2014), ANR-19-CE15-0028,LYMPHO-STING,Rôle de Sting dans le développement et les fonctions lymphocytaires(2019), and European Project: 677251,CD4DNASP
Subjects: CD4-Positive T-Lymphocytes, CD4-positive T lymphocytes, [SDV]Life Sciences [q-bio], TOR Serine-Threonine Kinases, Interleukin-9, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Membrane Proteins, Basic Tumor Immunology, Cell Differentiation, adaptive immunity, Th1 Cells, immunomodulation, eye diseases, Mice, Inbred C57BL, Mice, melanoma, Animals, Female, Interferon Regulatory Factor-3, Nucleotides, Cyclic, RC254-282, Signal Transduction
Abstract: International audience; Background While stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive. Methods Here, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances T H 9 cell antitumor activity against mouse melanoma upon adoptive transfer. Results We found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of T H 1 and T H 9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of T H 1 cell differentiation. However, STING activation favors T H 9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on T H 1 and T H 9-derived cytokines, and STING activation enhances the antitumor activity of T H 9 cells upon adoptive transfer. Conclusion Our results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.
Published: 2022
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19. How PET-CT is Changing the Management of Non-metastatic Castration-resistant Prostate Cancer?

Author: M. Baboudjian, M. Gauthé, E. Barret, L. Brureau, P. Rocchi, G. Créhange, C. Dariane, G. Fiard, G. Fromont, J.-B. Beauval, R. Mathieu, R. Renard-Penna, G. Roubaud, A. Ruffion, P. Sargos, M. Rouprêt, G. Ploussard, CHU Marseille, Centre Européen de Recherche en Imagerie médicale (CERIMED), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), Universitat Autònoma de Barcelona (UAB), Institut Mutualiste de Montsouris (IMM), CHU Pointe-à-Pitre/Abymes [Guadeloupe], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Curie [Paris], Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinique La Croix du Sud, CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Bergonié [Bordeaux], UNICANCER, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre pour l'innovation en cancérologie de Lyon (CICLY), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BAYER
Subjects: Prostate cancer, PET, Urology, PSMA, Non-metastatic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Castration-resistant
Abstract: International audience; Introduction: The aim of this narrative review conducted by the Prostate Cancer Committee of the French Association of Urology (CC-AFU) was to provide an update on the current evidence for the impact of PET/CT in the management of men with non-metastatic castration-resistant prostate cancer (nmCRPC). Material and methods: This review is based on data available in the literature on PET/CT imaging for staging nmCRPC patients. A PubMed search and narrative review of the data were performed in March 2022. Only articles in French or English were considered. Results: Current guidelines recommend bone scan and CT scan as standard imaging modalities for staging and follow-up of patients with nmCRPC. Nearly one-third of asymptomatic patients with presumed nmCRPC ultimately have metastatic disease on conventional imaging. Increasing reports have shown that conventional imaging has limited accuracy in detecting metastatic disease in nmCRPC patients, leading to the development of next-generation imaging techniques. In a retrospective study, F-18-choline PET/CT detected distant metastases in 27/58 high-risk nmCRPC patients with prior negative conventional imaging. The implementation of radiolabeled ligands of the prostate-speci c membrane antigen (PSMA) PET/CT in staging strategy has resulted in metastasis detection in 45% to 98% of patients with presumptive nmCRPC on conventional imaging. Such an early diagnosis of metastatic CRPC may allow patients to be referred for metastasis-directed therapies (i.e. stereotactic body radiotherapy), aimed at prolonging the ef cacy of systemic therapies and improving clinical outcomes. However, current data are not strong enough to recommend this strategy, which must be properly evaluated in clinical trials. Indeed, the use of molecular imaging may lead to inappropriate undertreatment if the secondgeneration androgen receptor inhibitors (darolutamide, enzalutamide, apalutamide), which prolong life, are not used in the subgroup of patients with high PSA velocity (PSA doubling time
Published: 2022
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20. A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy

Author: Jonathan Benzaquen, Jean Kanellopoulos, Nicolas Renault, Christophe Duranton, Cécile Delarasse, Sahil Adriouch, Alina Ghinet, Bernhard Ryffel, Christophe Furman, Régis Millet, Laetitia Seguin, Serena Janho Dit Hreich, Chloé C. Féral, Thierry Juhel, Julien Cherfils-Vicini, Paul Hofman, Germain Homerin, Xavier Dezitter, Valérie Vouret-Craviari, Laetitia Douguet, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Université de Lille, Droit et Santé, Laboratoire de PhysioMédecine Moléculaire (LP2M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hautes Etudes d’Ingénieur [Lille] (HEI), Institute for Research and Innovation in Biomedicine (IRIB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Alexandru Ioan Cuza University of Iași [Romania], Hôpital Pasteur [Nice] (CHU), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), JUNIA (JUNIA), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Gestionnaire, Hal Sorbonne Université, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, and Idex UCA JEDI - - UCA JEDI2015 - ANR-15-IDEX-0001 - IDEX - VALID
Subjects: 0301 basic medicine, Science, medicine.medical_treatment, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Mice, Transgenic, Article, General Biochemistry, Genetics and Molecular Biology, Small Molecule Libraries, Carcinoma, Lewis Lung, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cell Line, Tumor, Animals, Humans, Medicine, Receptor, Immune Checkpoint Inhibitors, Mice, Knockout, Multidisciplinary, Lung, Molecular Structure, business.industry, Activator (genetics), Purinergic receptor, Interleukin-18, General Chemistry, P2RX7, Immunotherapy, Combined Modality Therapy, Survival Analysis, Small molecule, Tumor Burden, 3. Good health, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, HEK293 Cells, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Tumour immunology, Female, Receptors, Purinergic P2X7, business
Abstract: Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor-bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a strategy that may be active against NSCLC., A limited percentage of patients with non-small cell lung cancer respond to immunotherapy. Here the authors show that HEI3090, a chemical positive modulator of the purinergic P2RX7 receptor, promotes IL-18 mediated anti-tumor immune responses and sensitizes lung cancer to anti-PD-1 therapy in preclinical models.
Published: 2021
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21. Chronic Pseudomonas aeruginosa Lung Infection Is IL-1R Independent, but Relies on MyD88 Signaling

Author: Dieudonnée Togbe, Jean-Claude Sirard, Corinne Panek, Jennifer Palomo, Marc Le Bert, Hana Čipčić Paljetak, Herbert B. Schiller, François Huaux, Thomas Secher, Tiffany Marchiol, Valérie F. J. Quesniaux, Tobias Stoeger, François Erard, Claire Mackowiak, Isabelle Couillin, Bernhard Ryffel, Louis Fauconnier, F. Savigny, Delphine Sedda, Alessandra Bragonzi, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Artimmune SAS, University of Zagreb, Artimmune, privé, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), IRCCS Ospedale San Raffaele [Milan, Italy], Université libre de Bruxelles (ULB), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Région Centre (ResPig project), CNRS of Orléans (France), and European funding in Région Centre-Val de Loire (FEDER 2016-00110366 BIO-TARGET, EX005756 BIO-TARGET II, and EUROFéRI EX010381)., Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), and Sirard, Jean-Claude
Subjects: Cell type, Myeloid, keratinocyte-derived chemokine, Pseudomonas aeruginosa, chronic lung infection, MyD88 signaling, [SDV]Life Sciences [q-bio], Immunology, MPO, knockout, Inflammation, medicine.disease_cause, Cystic fibrosis, Proinflammatory cytokine, Epithelial Damage, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, 030304 developmental biology, 0303 health sciences, biology, business.industry, KO, General Medicine, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], myeloperoxidase, medicine.anatomical_structure, Myeloperoxidase, biology.protein, medicine.symptom, business, 030215 immunology
Abstract: Cystic fibrosis is associated with chronic Pseudomonas aeruginosa colonization and inflammation. The role of MyD88, the shared adapter protein of the proinflammatory TLR and IL-1R families, in chronic P. aeruginosa biofilm lung infection is unknown. We report that chronic lung infection with the clinical P. aeruginosa RP73 strain is associated with uncontrolled lung infection in complete MyD88-deficient mice with epithelial damage, inflammation, and rapid death. Then, we investigated whether alveolar or myeloid cells contribute to heightened sensitivity to infection. Using cell-specific, MyD88-deficient mice, we uncover that the MyD88 pathway in myeloid or alveolar epithelial cells is dispensable, suggesting that other cell types may control the high sensitivity of MyD88-deficient mice. By contrast, IL-1R1–deficient mice control chronic P. aeruginosa RP73 infection and IL-1β Ab blockade did not reduce host resistance. Therefore, the IL-1R1/MyD88 pathway is not involved, but other IL-1R or TLR family members need to be investigated. Our data strongly suggest that IL-1 targeted neutralizing therapies used to treat inflammatory diseases in patients unlikely reduce host resistance to chronic P. aeruginosa infection.
Published: 2021
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22. When Bigger Is Better: 3D RNA Profiling of the Developing Head in the Catshark Scyliorhinus canicula

Author: Sylvie Mazan, Sébastien Déjean, Maxence Lanoizelet, Léo Michel, Arnaud Menuet, Kyle John Martin, Aurelie Quillien, Ronan Lagadec, Hélène Mayeur, Patrick Blader, Biologie intégrative des organismes marins (BIOM), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Observatoire océanologique de Banyuls (OOB), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Unité de biologie moléculaire, cellulaire et du développement - UMR5077 (MCD), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Biotechnology and Biological Sciences Research Council (BBSRC), Institut de Mathématiques de Toulouse UMR5219 (IMT), Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE13-0013,AsymmetricBrain,Origine et diversification des asymétries cérébrales chez les vertébrés(2016), Unité de biologie moléculaire, cellulaire et du développement (MCD), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Biotechnology and Biological Sciences Research Council, Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3)
Subjects: QH301-705.5, ved/biology.organism_classification_rank.species, Computational biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Genome, auto-correlation, 03 medical and health sciences, 0302 clinical medicine, RNA tomography, Biology (General), Model organism, Gene, Zebrafish, 030304 developmental biology, 0303 health sciences, catshark, Phylogenetic tree, biology, ved/biology, Scyliorhinus canicula, Cell Biology, biology.organism_classification, Catshark, Gene expression profiling, forebrain patterning, correlation, 030217 neurology & neurosurgery, Developmental Biology
Abstract: We report the adaptation of RNA tomography, a technique allowing spatially resolved, genome-wide expression profiling, to a species occupying a key phylogenetic position in gnathostomes, the catshark Scyliorhinus canicula. We focused analysis on head explants at an embryonic stage, shortly following neural tube closure and of interest for a number of developmental processes, including early brain patterning, placode specification or the establishment of epithalamic asymmetry. As described in the zebrafish, we have sequenced RNAs extracted from serial sections along transverse, horizontal and sagittal planes, mapped the data onto a gene reference taking advantage of the high continuity genome recently released in the catshark, and projected read counts onto a digital model of the head obtained by confocal microscopy. This results in the generation of a genome-wide 3D atlas, containing expression data for most protein-coding genes in a digital model of the embryonic head. The digital profiles obtained for candidate forebrain regional markers along antero-posterior, dorso-ventral and left-right axes reproduce those obtained by in situ hybridization (ISH), with expected relative organizations. We also use spatial autocorrelation and correlation as measures to analyze these data and show that they provide adequate statistical tools to extract novel expression information from the model. These data and tools allow exhaustive searches of genes exhibiting any predefined expression characteristic, such a restriction to a territory of interest, thus providing a reference for comparative analyses across gnathostomes. This methodology appears best suited to species endowed with large embryo or organ sizes and opens novel perspectives to a wide range of evo-devo model organisms, traditionally counter-selected on size criterion.
Published: 2021
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23. STING signaling and sterile inflammation

Author: Isabelle Couillin, Nicolas Riteau, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: Cytoplasm, [SDV]Life Sciences [q-bio], Cell, Review, Adenosine Triphosphate, 0302 clinical medicine, self-DNA, Neoplasms, Immunology and Allergy, Receptor, 0303 health sciences, NF-kappa B, Neurodegenerative Diseases, Nucleotidyltransferases, Mitochondria, 3. Good health, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Stimulator of interferon genes, Interferon Type I, Cytokines, Guanosine Triphosphate, Nucleotides, Cyclic, Signal Transduction, Adult, Cell physiology, Programmed cell death, autophagy, Immunology, Biology, Autoimmune Diseases, 03 medical and health sciences, medicine, Humans, 030304 developmental biology, Inflammation, Innate immune system, Autophagy, Infant, Membrane Proteins, DNA, RC581-607, Immunity, Innate, eye diseases, Sting, sterile inflammation, Immunologic diseases. Allergy, type I IFN, STING, cGAS
Abstract: International audience; Innate immunity is regulated by a broad set of evolutionary conserved receptors to finely probe the local environment and maintain host integrity. Besides pathogen recognition through conserved motifs, several of these receptors also sense aberrant or misplaced self-molecules as a sign of perturbed homeostasis. Among them, selfnucleic acid sensing by the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway alerts on the presence of both exogenous and endogenous DNA in the cytoplasm. We review recent literature demonstrating that self-nucleic acid detection through the STING pathway is central to numerous processes, from cell physiology to sterile injury, auto-immunity and cancer. We address the role of STING in autoimmune diseases linked to dysfunctional DNAse or related to mutations in DNA sensing pathways. We expose the role of the cGAS/STING pathway in inflammatory diseases, neurodegenerative conditions and cancer. Connections between STING in various cell processes including autophagy and cell death are developed. Finally, we review proposed mechanisms to explain the sources of cytoplasmic DNA.
Published: 2021
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24. Deletion of Mocos induces xanthinuria with obstructive nephropathy and major metabolic disorders in mice

Author: Madeleine Erard-Garcia, Sylvie Mavel, Ana Dudas, Michael J. Mihatsch, Julie Pailloux, Claire Mackowiak, Frédéric Foucher, Pauline Rontani, Nicolas Erard, Elodie Culerier, Bernhard Ryffel, Marc Le Bert, Valérie F. J. Quesniaux, Delphine Sedda, Antoine Lefevre, Patrick Emond, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: Purine, Purine-Pyrimidine Metabolism, Inborn Errors, medicine.medical_specialty, Tamm–Horsfall protein, Xanthine Dehydrogenase, [SDV]Life Sciences [q-bio], Supervision, Xanthine, Pathogenesis, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Urolithiasis, Formal analysis, Internal medicine, Validation, medicine, Animals, Xanthinuria, Purine metabolism, Original Investigation, 030304 developmental biology, Investigation, 0303 health sciences, biology, Data curation, business.industry, Molybdenum cofactor sulfurase, General Medicine, medicine.disease, Obstructive Nephropathy, 3. Good health, Endocrinology, chemistry, Writing -original draft, biology.protein, Kidney Diseases, business, Project administration, 030217 neurology & neurosurgery
Abstract: Background Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder. Methods Mice with targeted disruption of the molybdenum cofactor sulfurase (Mocos) gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism. Results Mocos-deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilation, Tamm–Horsfall (uromodulin) protein (THP) deposits, tubular cell necrosis with neutrophils, and occasionally hydronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems, and important alterations of the metabolism of purines, amino acids, and phospholipids. Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology. Conclusions Mocos-deficient mice develop a lethal obstructive nephropathy associated with profound metabolic changes. Studying MOCOS functions may provide important clues about the underlying pathogenesis of xanthinuria and other diseases requiring early diagnosis.
Published: 2021
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25. Dietary Supplement Enriched in Antioxidants and Omega-3 Promotes Glutamine Synthesis in Müller Cells: A Key Process against Oxidative Stress in Retina

Author: Khaoula Ramchani Ben Othman, Arnaud Pâris, Rafaëlle Rossignol, Sylvain Briault, Chloé Felgerolle, Maryvonne Ardourel, Olivier Perche, Isabelle Ranchon-Cole, Natsuko Ueda, Niyazi Acar, Betty Hébert, Audrey Bazinet, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Clermont-Ferrand, Centre Hospitalier Régional d'Orléans (CHRO), CNRS Orléans, Regional Hospital of Orléans, University of Orléans, University of Clermont-Ferrand, INSERM Clermont-Ferrand., and Anna Gramza-Michałowska
Subjects: Nutritional Supplementation, Cell Survival, Ependymoglial Cells, Glutamic Acid, glutamate, Oxidative phosphorylation, Resveratrol, medicine.disease_cause, Article, Antioxidants, Retina, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, In vivo, Fatty Acids, Omega-3, medicine, Animals, oxidative stress, TX341-641, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Unsaturated fatty acid, Cells, Cultured, 030304 developmental biology, Müller cells, 0303 health sciences, Nutrition and Dietetics, Chemistry, Nutrition. Foods and food supply, Glutamate receptor, Culture Media, Glutamine, Biochemistry, Gene Expression Regulation, nutritional supplementation, glutamine, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Oxidative stress, Food Science
Abstract: International audience; To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, only one preclinical study has evaluated the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina and demonstrated that in vivo supplementation prevents the retina from structural and functional injuries induced by light. Considering the crucial role played by the glial Müller cells in the retina, particularly to regulate the glutamate cycle to prevent damage in oxidative stress conditions, we questioned the impact of this ocular supplement on the glutamate metabolic cycle. To this end, various molecular aspects associated with the glutamate/glutamine metabolism cycle in Müller cells were investigated on primary Müller cells cultures incubated, or not, with the commercially mix supplement before being subjected, or not, to oxidative conditions. Our results demonstrated that in vitro supplementation provides guidance of the glutamate/glutamine cycle in favor of glutamine synthesis. These results suggest that glutamine synthesis is a crucial cellular process of retinal protection against oxidative damages and could be a key step in the previous in vivo beneficial results provided by the dietary supplementation.
Published: 2021
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26. Microbial metabolites control the thymic development of mucosal-associated invariant T cells

Author: Manal Sarkis, Jules Gilet, Kristina Niort, François Legoux, Yara El Morr, Olivier Lantz, Emanuele Procopio, Aurélie Balvay, Ahmed El Marjou, Aurélie Darbois, Frédéric Schmidt, Anne Foussier, Déborah Bellet, Celine Daviaud, Marion Salou, Sylvie Rabot, Bernhard Ryffel, Recherches en cancérologie, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et cancer (U932), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV]Life Sciences [q-bio], Receptors, Antigen, T-Cell, Thymus Gland, Mucosal associated invariant T cell, Major histocompatibility complex, medicine.disease_cause, Mucosal-Associated Invariant T Cells, Minor Histocompatibility Antigens, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Escherichia coli, medicine, [CHIM]Chemical Sciences, Animals, Germ-Free Life, Symbiosis, Uracil, Receptor, Lung, ComputingMilieux_MISCELLANEOUS, Ribitol, 030304 developmental biology, Mice, Knockout, Orphan receptor, 0303 health sciences, Mucous Membrane, Multidisciplinary, biology, Escherichia coli Proteins, Histocompatibility Antigens Class I, biology.organism_classification, Gastrointestinal Microbiome, Specific Pathogen-Free Organisms, Cell biology, Mice, Inbred C57BL, Nucleotide Deaminases, biology.protein, Spleen, Bacteria, Sugar Alcohol Dehydrogenases, 030215 immunology
Abstract: Commensals rule the MAITrix Mucosal-associated invariant T (MAIT) cells play an important role in mucosal homeostasis. MAIT cells recognize microbial small molecules presented by the major histocompatibility complex class Ib molecule MR1. MAIT cells are absent in germ-free mice, and the mechanisms by which microbiota control MAIT cell development are unknown (see the Perspective by Oh and Unutmaz). Legoux et al. show that, in mice, development of MAIT cells within the thymus is governed by the bacterial product 5-(2-oxopropylideneamino)-6- d -ribitylaminouracil, which rapidly traffics from the mucosa to the thymus, where it is captured by MR1 and presented to developing MAIT cells. Constantinides et al. report that MAIT cell induction only occurs during a limited, early-life window and requires exposure to defined microbes that produce riboflavin derivatives. Continual interactions between MAIT cells and commensals in the skin modulates tissue repair functions. Together, these papers highlight how the microbiota can direct immune cell development and subsequent function at mucosal sites by secreting compounds that act like self-antigens. Science , this issue p. 494 , p. eaax6624 ; see also p. 419
Published: 2019
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27. Epigenetic regulation clocks the multigenerational olfactory imprinting in C. elegans

Author: Antoine Gruet, Jean-Jacques Remy, Yoanne M. Clovis, Francois Feron, Kévin Baranger, Diana Andrea Fernandes De Abreu, Madeleine Erard-Garcia, Marie-Pierre Blanchard, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Institut Sophia Agrobiotech (ISA), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Côte d'Azur (UCA), Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA, Regional Imaging Platform, Montpellier Ressources Imagerie (MRI), BioCampus, Montpellier, France, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Nemametrix Inc., Eugene, Oregon, USA, Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), BioCampus (BCM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, Candidate gene, biology, Period (gene), Translation (biology), Cell biology, 03 medical and health sciences, 0302 clinical medicine, biology.protein, Demethylase, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Histone deacetylase, Epigenetics, Imprinting (psychology), Transcription factor, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Imprinting is an early sensory life experience that induces adult behaviours, such as mother recognition or homing. In a previous study, we demonstrated a striking olfactory imprinting in C. elegans that can be inherited over generations. When exposed to specific odorants during a timely controlled post-hatch period, C. elegans worms display during adulthood an enhanced migration towards these molecules. In order to unveil some of the genetic and epigenetic factors that are responsible for such a behavioural plasticity, we assessed the role of heterochronic genes using a candidate gene approach. We report here that translation of the Hunchback-Like 1 (HBL1) transcription factor in the sensory processing interneuron AIY, is a determining factor for olfactory plasticity timing in C.elegans. HBL1 may associate to the SPR1/CoREST co-repressor, the lysine demethylase SPR5/LSD1 and the histone deacetylase HDA3 to lengthen the plasticity period, whereas the translation initiation factor IFE-4 and the histone deacetylase HDA2 abridge it. We also observed that lengthened plasticity periods allow proportionally faster stable behavioral adaptation of C. elegans populations. We conclude that plasticity timing is a key factor, not only to transiently adapt individuals but also to stably adapt animal populations via multigenerational accumulation of experience.
Published: 2021
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28. Aryl hydrocarbon receptor ( Ahr )‐dependent Il‐22 expression by type 3 innate lymphoid cells control of acute joint inflammation

Author: Nehmar, Ramzi, Fauconnier, Louis, Alves‐Filho, Jose, Togbe, Dieudonnée, DeCauwer, Aurore, Bahram, Seiamak, Le Bert, Marc, Ryffel, Bernhard, Georgel, Philippe, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Inflammation, Mice, Knockout, aryl hydrocarbon receptor, acute arthritis, Interleukins, IL‐22, Original Articles, respiratory system, Arthritis, Experimental, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Immunity, Innate, Mice, Inbred C57BL, Mice, Receptors, Aryl Hydrocarbon, Acute Disease, Basic Helix-Loop-Helix Transcription Factors, Animals, Original Article, Female, Joints, Lymphocytes
Abstract: International audience; The aryl hydrocarbon receptor (AHR) controls several inflammatory and metabolic pathways involved in various diseases, including the development of arthritis. Here, we investigated the role of AHR activation in IL-22-dependent acute arthritis using the K/BxN serum transfer model. We observed an overall reduction of cytokine expression in Ahr-deficient mice, along with decreased signs of joint inflammation. Conversely, we report worsened arthritis symptoms in Il-22 deficient mice. Pharmacological stimulation of AHR with the agonist VAG539, as well as injection of recombinant IL-22, given prior arthritogenic triggering, attenuated inflammation and reduced joint destruction. The protective effect of VAG539 was abrogated in Il-22 deficient mice. Finally, conditional Ahr depletion of Rorc-expressing cells was sufficient to attenuate arthritis, thereby uncovering a previously unsuspected role of AHR in type 3 innate lymphoid cells during acute arthritis.
Published: 2021
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29. Gasdermins mediate cellular release of mitochondrial DNA during pyroptosis and apoptosis

Author: Carlos de Torre-Minguela, Pablo Pelegrín, Ana I. Gomez, Isabelle Couillin, UMR7355 Immunologie et Neurogénétique Expérimentales et Moléculaires, Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitario Virgen de la Arrixaca, Universidad de Murcia, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: Mitochondrial DNA, Programmed cell death, Inflammasomes, [SDV]Life Sciences [q-bio], Apoptosis, mitochondrial DNA, Mitochondrion, In Vitro Techniques, Biochemistry, DNA, Mitochondrial, 03 medical and health sciences, Mice, 0302 clinical medicine, NLR Family, Pyrin Domain-Containing 3 Protein, Genetics, Pyroptosis, Animals, Humans, Inner mitochondrial membrane, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Chemistry, Macrophages, Intrinsic apoptosis, Cell Membrane, Intracellular Signaling Peptides and Proteins, Phosphate-Binding Proteins, Pyrin, Cell biology, Mitochondria, Mice, Inbred C57BL, Cytosol, HEK293 Cells, Receptors, Estrogen, Caspases, GSDME, GSDMD, 030217 neurology & neurosurgery, Biotechnology
Abstract: International audience; Pyroptosis and intrinsic apoptosis are two forms of regulated cell death driven by active caspases where plasma membrane permeabilization is induced by gasdermin pores. Caspase-1 induces gasdermin D pore formation during pyroptosis, whereas caspase-3 promotes gasdermin E pore formation during apoptosis. These two types of cell death are accompanied by mitochondrial outer membrane permeabilization due to BAK/BAX pore formation in the external membrane of mitochondria, and to some extent, this complex also affects the inner mitochondrial membrane facilitating mitochondrial DNA relocalization from the matrix to the cytosol. However, the detailed mechanism responsible for this process has not been investigated. Herein, we reported that gasdermin processing is required to induce mitochondrial DNA release from cells during pyroptosis and apoptosis. Gasdermin targeted at the plasma membrane promotes a fast mitochondrial collapse along with the initial accumulation of mitochondrial DNA in the cytosol and then facilitates the DNA's release from the cell when the plasma membrane ruptures. These findings demonstrate that gasdermin action has a critical effect on the plasma membrane and facilitates the release of mitochondrial DNA as a damage-associated molecular pattern.
Published: 2021
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30. Natterin an aerolysin-like fish toxin drives IL--dependent neutrophilic inflammation mediated by caspase-1 and caspase-11 activated by the inflammasome sensor NLRP6

Author: Lima, Carla, Falcao, Maria Alice Pimentel, Andrade-Barros, Aline Ingrid, Seni-Silva, Ana Carolina, Grund, Lidiane Zito, Balogh, Eniko, Conceiçao, Katia, Quesniaux, Valérie, Ryffel, Bernhard, Lopes-Ferreira, Monica, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: aerolysin, Natterin, IL-1, [SDV]Life Sciences [q-bio], neutrophilia, caspase-11/caspase-1, NLPR6/NLRC4, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021
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31. Protective role of the nucleic acid sensor STING in pulmonary fibrosis Running title: STING protects against IPF

Author: Savigny, Florence, Schricke, Corinne, Lacerda-Queiroz, Norinne, Meda, Mélanie, Nascimento, Mégane, Huot-Marchand, Sarah, Da Gama Monteiro, Felipe, Ryffel, Bernhard, Gombault, Aurélie, Le Bert, M, Couillin, Isabelle, Riteau, Nicolas, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: IL-28, mice, [SDV]Life Sciences [q-bio], respiratory system, idiopathic pulmonary fibrosis, self-DNA recognition, eye diseases, respiratory tract diseases, STING
Abstract: International audience; Idiopathic pulmonary fibrosis (IPF) is the most common and severe type of interstitial lung disease for which current treatments display limited efficacy. IPF is largely driven by host-derived danger signals released upon recurrent local tissue damage. Here we explored the roles of self-DNA and stimulator of interferon genes (STING), a protein belonging to an intracellular DNA sensing pathway that leads to type I and/or type III interferon (IFN) production upon activation. Using a mouse model of IPF, we report that STING deficiency leads to exacerbated pulmonary fibrosis with increased collagen deposition in the lungs and excessive remodeling factors expression. We further show that STING-mediated protection does not rely on type I IFN signaling nor on IL-17A or TGF-β modulation but is associated with dysregulated neutrophils. Together, our data support an unprecedented immunoregulatory function of STING in lung fibrosis.
Published: 2021
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32. Bromodomain and extraterminal (BET) protein inhibition of IgG/IgE production in murine B cells is counter-balanced by a strong Th2 bias

Author: Bernhard Ryffel, Yolla Makhour, Zeinab Dalloul, Pauline Chenuet, Jean-Claude Aldigier, Michel Cogné, François Boyer, Marie Best, Valérie F. J. Quesniaux, Sandrine Le Noir, Dieudonnée Togbe, Jeanne Cook-Moreau, Mylène Gador, Nicolas Fazilleau, Iman Dalloul, Jonchère, Laurent, Rôle de la classe des Ig / BCR dans les interactions cellulaires supportant la mémoire immune et impact immunopathologique - - Ig-MemImpact2016 - ANR-16-CE15-0019 - AAPG2016 - VALID, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Artimmune SAS, Lebanese University [Beirut] (LU), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), PGA1 RF20180207070, Fondation ARC pour la Recherche sur le Cancer, ANR‐16‐CE15‐0019‐01, Agence Nationale de la Recherche, 2016‐00110366, European Regional Development Fund, ANR-16-CE15-0019,Ig-MemImpact,Rôle de la classe des Ig / BCR dans les interactions cellulaires supportant la mémoire immune et impact immunopathologique(2016), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: 0301 basic medicine, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immunoglobulin E, immune response, Allergic inflammation, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, allergic inflammation, Immunology and Allergy, General Nursing, biology, Chemistry, RC581-607, Eosinophil, Bromodomain, 030104 developmental biology, medicine.anatomical_structure, Immunoglobulin class switching, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Humoral immunity, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Original Article, Immunologic diseases. Allergy, Antibody, bromodomain inhibition, antibody class switching, 030215 immunology
Abstract: Objectives Inhibitors of bromodomain and extra terminal domain (BET) proteins are a new and growing class of anti‐cancer drugs, which decrease oncogene expression by targeting superenhancers. Antibody production is another physiological process relying on superenhancers, and it remains to be clarified whether potential immunomodulatory properties of BET inhibitors might impact humoral immunity and allergy. Methods We thus evaluated humoral immune responses and their Th2 context in vitro and in vivo in mice following treatment with the classical BET‐inhibitor JQ1. We quantified immunoglobulin (Ig) and antibody production by B cells either stimulated in vitro or obtained from immunised mice. JQ1 effects on class switching and activation‐induced deaminase loading were determined, together with modifications of B, T follicular helper (Tfh) and T helper 2 (Th2) populations. JQ1 was finally tested in B‐cell‐dependent models of immune disorders. Results Bromodomain and extra terminal domain inhibition reduced class switching, Ig expression on B cells and antibody secretion and was correlated with decreased numbers of Tfh cells. However, JQ1 strongly increased the proportion of GATA3+ Th2 cells and the secretion of corresponding cytokines. In a mouse allergic model of lung inflammation, JQ1 did not affect eosinophil infiltration or mucus production but enhanced Th2 cytokine production and aggravated clinical manifestations. Conclusion Altogether, BET inhibition thus interweaves intrinsic negative effects on B cells with a parallel complex reshaping of T‐cell polarisation which can increase type 2 cytokines and eventually promote B‐cell‐dependent immunopathology. These opposite and potentially hazardous immunomodulatory effects raise concerns for clinical use of BET inhibitors in patients with immune disorders., While bromodomain and extra terminal domain inhibition reduces class switching, antibody secretion and T follicular helper cell number, this treatment increases the proportion of GATA3+ T helper 2 cells and the secretion of corresponding cytokines. In a mouse model of lung inflammation, JQ1 thus aggravates rather than improves clinical manifestations.
Published: 2021
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33. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade

Author: Carolina Alves Costa Silva, Deborah Lefevre, Lisa Derosa, Claudia Grajeda-Iglesias, Gladys Ferrere, Maryam Tidjani Alou, Anne-Gaëlle Goubet, Fanny Aprahamian, Conrad Rauber, Didier Raoult, Aurélie Fluckiger, Monica Arnedos, Damien Drubay, Romain Daillère, Cassandra Thelemaque, Tim D. Spector, Sylvère Durand, Liwei Zhao, Guido Kroemer, Emeline Colomba, Oliver Kepp, Valerio Iebba, Laurence Zitvogel, Nicola Segata, Francesco Asnicar, Marine Fidelle, Peng Liu, Bernhard Ryffel, Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Università degli studi di Trieste = University of Trieste, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Oncologie gynécologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pathologie mammaire, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], King‘s College London, Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, Ferrere, G., Alou, M. T., Liu, P., Goubet, A. -G., Fidelle, M., Kepp, O., Durand, S., Iebba, V., Fluckiger, A., Daillere, R., Thelemaque, C., Grajeda-Iglesias, C., Silva, C. A. C., Aprahamian, F., Lefevre, D., Zhao, L., Ryffel, B., Colomba, E., Arnedos, M., Drubay, D., Rauber, C., Raoult, D., Asnicar, F., Spector, T., Segata, N., Derosa, L., Kroemer, G., Zitvogel, L., Gestionnaire, Hal Sorbonne Université, LUMIERE - - LUMIERE2016 - ANR-16-RHUS-0008 - RHUS - VALID, European Union’s Horizon 2020 research and innovation programme under grant agreement. - ONCOBIOME - 825410 - INCOMING, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), University of Trieste, Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Ketogenic, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Programmed Cell Death 1 Receptor, Cancer, Immunotherapy, Metabolism, Mouse models, Oncology, 3-Hydroxybutyric Acid, Animals, CTLA-4 Antigen, Cell Line, Tumor, Combined Modality Therapy, Female, Gastrointestinal Microbiome, Humans, Immune Checkpoint Inhibitors, Ketone Bodies, Kidney Neoplasms, Melanoma, Experimental, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, Receptors, G-Protein-Coupled, Diet, Ketogenic, Pharmacology, CXCR3, Inbred C57BL, 0302 clinical medicine, Neoplasms, Ketogenesis, Receptors, Ketone Bodie, Melanoma, Inbred BALB C, Tumor, Chemistry, Kidney Neoplasm, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], Immunosurveillance, 030220 oncology & carcinogenesis, Ketone bodies, Medicine, Human, Research Article, Immune Checkpoint Inhibitor, Mouse model, Cell Line, 03 medical and health sciences, Experimental, G-Protein-Coupled, Downregulation and upregulation, medicine, Animal, Immune checkpoint, Diet, 030104 developmental biology, Ketogenic diet
Abstract: International audience; Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.
Published: 2021
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34. Sepsis expands a CD39 + plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity

Author: Paulo Henrique Melo, Luisa Menezes-Silva, Fernando Q. Cunha, Marcos C. Borges, Bernhard Ryffel, Daniel Zoppi, Ícaro Maia Santos de Castro, Juliana E Toller-Kawahisa, Diego B. Caetite, Paula Ramos Viacava, Antonio Edson Rocha Oliveira, Raphael S. Peres, Helder I. Nakaya, Daniele C. Nascimento, Joel Linden, Thiago M. Cunha, Dario S. Zamboni, Gilles Kauffenstein, José C. Alves-Filho, Raphael Gomes Ferreira, Valérie F. J. Quesniaux, Denise Morais da Fonseca, Flávio P. Veras, Paula B. Donate, Annie R. Piñeros, Jonas Augusto Rizzato Paschoal, Marina Alves Damaceno, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: MACRÓFAGOS, [SDV]Life Sciences [q-bio], Secondary infection, medicine.medical_treatment, Immunology, Population, Biology, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, Macrophage, education, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, B cells, 0303 health sciences, education.field_of_study, immunosuppression, Immunosuppression, medicine.disease, Adenosine, macrophages, 3. Good health, Interleukin 10, Infectious Diseases, adenosine, 030220 oncology & carcinogenesis, plasmablast, medicine.drug
Abstract: Sepsis results in elevated adenosine in circulation. Extracellular adenosine triggers immunosuppressive signaling via the A2a receptor (A2aR). Sepsis survivors develop persistent immunosuppression with increased risk of recurrent infections. We utilized the cecal ligation and puncture (CLP) model of sepsis and subsequent infection to assess the role of adenosine in post-sepsis immune suppression. A2aR-deficient mice showed improved resistance to post-sepsis infections. Sepsis expanded a subset of CD39hi B cells and elevated extracellular adenosine, which was absent in mice lacking CD39-expressing B cells. Sepsis-surviving B cell-deficient mice were more resistant to secondary infections. Mechanistically, metabolic reprogramming of septic B cells increased production of ATP, which was converted into adenosine by CD39 on plasmablasts. Adenosine signaling via A2aR impaired macrophage bactericidal activity and enhanced interleukin-10 production. Septic individuals exhibited expanded CD39hi plasmablasts and adenosine accumulation. Our study reveals CD39hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease.
Published: 2021
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35. Acetylcholine production by type 2 innate lymphoid cells promotes mucosal immunity to helminth parasites

Author: Roberts, Luke, Schnoeller, Corinna, Berkachy, Rita, Darby, Matthew, Pillaye, Jamie, Oudhoff, Menno, Parmar, Naveen, Mackowiak, Claire, Sedda, Delphine, Quesniaux, Valérie, Ryffel, Bernhard, Vaux, Rachel, Gounaris, Kleoniki, Berrard, Sylvie, Withers, David, Horsnell, William G C, Selkirk, Murray, Imperial College London, University of Cape Town, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Birmingham [Birmingham], Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Quesniaux, Valérie
Subjects: [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
Abstract: International audience; Innate lymphoid cells (ILCs) are critical mediators of immunological and physiological responses at mucosal barrier sites. While neurotransmitters can stimulate ILCs, the synthesis of small-molecule neurotransmitters by these cells has only recently begun to be appreciated. Type 2 innate lymphoid cells (ILC2s) are shown here to synthesise and release acetylcholine (ACh) during parasitic nematode infection. The cholinergic phenotype of pulmonary ILC2s was associated with their activation state, could be induced by in vivo exposure to extracts of Alternaria alternata or the alarmin cytokines interleukin (IL)-33 and IL-25, and was augmented by IL-2 in vitro. Genetic disruption of ACh synthesis by murine ILC2s resulted in increased parasite burdens, impaired ILC2 proliferation, and reduced features of lung and gut barrier responses following Nippostrongylus brasiliensis infection. These data demonstrate a functional role for ILC2-derived ACh in expansion of ILC2s for maximal induction of type 2 immunity.
Published: 2021
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36. Silica-related diseases in the modern world: a role for self-DNA sensing in lung inflammatory diseases

Author: Dieudonnée Togbe, Valérie F. J. Quesniaux, Sulayman Benmerzoug, Bernhard Ryffel, Muazzam Jacobs, Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Institute of Infectious Diseases and Molecular Medicine (IDM), and University of Cape Town
Subjects: Lung Diseases, [SDV]Life Sciences [q-bio], Immunology, Inflammation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Humans, Immunology and Allergy, Medicine, Lung, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Innate immune system, business.industry, DNA, Silicon Dioxide, 3. Good health, medicine.anatomical_structure, chemistry, medicine.symptom, business, 030215 immunology
Abstract: International audience
Published: 2020
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37. Fucoxanthin, a Marine-Derived Carotenoid from Brown Seaweeds and Microalgae: A Promising Bioactive Compound for Cancer Therapy

Author: Sarah Méresse, Mostefa Fodil, Fabrice Fleury, Benoît Chénais, Mer, molécules et santé EA 2160 (MMS), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN)-Le Mans Université (UM)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN), Unité de fonctionnalité et ingénierie de protéines (UFIP), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: Aquatic Organisms, Epithelial-Mesenchymal Transition, natural products, Anti-Inflammatory Agents, DNA repair, Angiogenesis Inhibitors, Antineoplastic Agents, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Review, Xanthophylls, migration, fucoxanthin, lcsh:Chemistry, angiogenesis, Cell Movement, Autophagy, Microalgae, Humans, cancer, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:QH301-705.5, Cell Proliferation, Clinical Trials as Topic, Molecular Structure, EMT, Cell Cycle Checkpoints, cell growth arrest, Seaweed, invasion, Treatment Outcome, lcsh:Biology (General), lcsh:QD1-999, inflammation, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, DNA Damage
Abstract: International audience; Fucoxanthin is a well-known carotenoid of the xanthophyll family, mainly produced by marine organisms such as the macroalgae of the fucus genus or microalgae such as Phaeodactylum tricornutum. Fucoxanthin has antioxidant and anti-inflammatory properties but also several anticancer effects. Fucoxanthin induces cell growth arrest, apoptosis, and/or autophagy in several cancer cell lines as well as in animal models of cancer. Fucoxanthin treatment leads to the inhibition of metastasis-related migration, invasion, epithelial-mesenchymal transition, and angiogenesis. Fucoxanthin also affects the DNA repair pathways, which could be involved in the resistance phenotype of tumor cells. Moreover, combined treatments of fucoxanthin, or its metabolite fucoxanthinol, with usual anticancer treatments can support conventional therapeutic strategies by reducing drug resistance. This review focuses on the current knowledge of fucoxanthin with its potential anticancer properties, showing that fucoxanthin could be a promising compound for cancer therapy by acting on most of the classical hallmarks of tumor cells.
Published: 2020
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38. Regulation of IL (Interleukin)-33 Production in Endothelial Cells via Kinase Activation and Fas/CD95 Upregulation

Author: Valérie Ledroit, Philippe Marquillies, Catherine Duez, Barbara Gross, Corine Glineur, Bernhard Ryffel, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), The research was supported by Grants from Société française d’Allergologie and Région Hauts-de-France. C. Duez, B. Gross, and C. Glineur are researchers of Institut National de la Santé et de la Recherche Médicale, Université Nord de France, and Centre National de la Recherche Scientifique (CNRS), respectively. B. Ryffel is research director at CNRS. P. Marquillies and V. Ledroit are technicians of Institut Pasteur de Lille., Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), and Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, endothelium, Endothelium, [SDV]Life Sciences [q-bio], Inflammation, Cell Line, blood vessels, 03 medical and health sciences, Mice, 0302 clinical medicine, Downregulation and upregulation, medicine, Human Umbilical Vein Endothelial Cells, Animals, Humans, Antigens, Dermatophagoides, fas Receptor, Lung, Wnt Signaling Pathway, Caspase 8, Kinase, business.industry, Endothelial Cells, Fas receptor, Interleukin-33, 3. Good health, Up-Regulation, Interleukin 33, Enzyme Activation, 030104 developmental biology, medicine.anatomical_structure, inflammation, Immunology, medicine.symptom, Phosphatidylinositol 3-Kinase, Cardiology and Cardiovascular Medicine, business, Proto-Oncogene Proteins c-akt, 030215 immunology, Blood vessel
Abstract: Objective: The occurrence of new blood vessel formation in the lungs of asthmatic patients suggests a critical role for airway endothelial cells (ECs) in the disease. IL-33 (Interleukin-33)—a cytokine abundantly expressed in human lung ECs—recently emerged as a key factor in the development of allergic diseases, including asthma. In the present study, we evaluated whether mouse and human ECs exposed to the common Dermatophagoides farinae allergen produce IL-33 and characterized the activated signaling pathways. Approach and Results: Mouse primary lung ECs were exposed in vitro to D farinae extract or rmIL-33 (recombinant murine IL-33). Both D farinae and rmIL-33 induced Il-33 transcription without increasing the IL-33 production and upregulated the expression of its receptor, as well as genes involved in angiogenesis and the regulation of immune responses. In particular, D farinae and rmIL-33 upregulated Fas/Cd95 transcript level, yet without promoting apoptosis. Inhibition of caspases involved in the Fas signaling pathway, increased IL-33 protein level in ECs, suggesting that Fas may decrease IL-33 level through caspase-8-dependent mechanisms. Our data also showed that the NF-κB (nuclear factor-κB), PI3K/Akt, and Wnt/β-catenin pathways regulate Il-33 transcription in both mouse and human primary ECs. Conclusions: Herein, we described a new mechanism involved in the control of IL-33 production in lung ECs exposed to allergens.
Published: 2020
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39. Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments

Author: Dieudonnée Togbe, Valérie F. J. Quesniaux, Sylvain Briault, Flora Reverchon, Arnaud Menuet, Bernhard Ryffel, Sulayman Benmerzoug, Vidian de Concini, Vanessa Larrigaldie, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Artimmune SAS, Quesniaux, Valérie, and Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], Immunology, Central nervous system, Minocycline, Hippocampal formation, Hippocampus, lcsh:RC346-429, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Memory, Animals, Medicine, Cognitive Dysfunction, lcsh:Neurology. Diseases of the nervous system, Neuroinflammation, Spatial Memory, 030304 developmental biology, Inflammation, Mice, Knockout, 0303 health sciences, Microglia, business.industry, Research, General Neuroscience, Interleukin, Cell sorting, Interleukin-33, [SDV] Life Sciences [q-bio], Interleukin 33, medicine.anatomical_structure, Neurology, Cell activation, business, Neuroscience, 030217 neurology & neurosurgery, Interleukin-1
Abstract: Background Interleukin (IL)-33 is expressed in a healthy brain and plays a pivotal role in several neuropathologies, as protective or contributing to the development of cerebral diseases associated with cognitive impairments. However, the role of IL-33 in the brain is poorly understood, raising the question of its involvement in immunoregulatory mechanisms. Methods We administered recombinant IL-33 (rmIL-33) by intra-hippocampal injection to C57BL/6 J (WT) and IL-1αβ deficient mice. Chronic minocycline administration was performed and cognitive functions were examined trough spatial habituation test. Hippocampal inflammatory responses were investigated by RT-qPCR. The microglia activation was assessed using immunohistological staining and fluorescence-activated cell sorting (FACS). Results We showed that IL-33 administration in mice led to a spatial memory performance defect associated with an increase of inflammatory markers in the hippocampus while minocycline administration limited the inflammatory response. Quantitative assessment of glial cell activation in situ demonstrated an increase of proximal intersections per radius in each part of the hippocampus. Moreover, rmIL-33 significantly promoted the outgrowth of microglial processes. Fluorescence-activated cell sorting analysis on isolated microglia, revealed overexpression of IL-1β, 48 h post-rmIL-33 administration. This microglial reactivity was closely related to the onset of cognitive disturbance. Finally, we demonstrated that IL-1αβ deficient mice were resistant to cognitive disorders after intra-hippocampal IL-33 injection. Conclusion Thus, hippocampal IL-33 induced an inflammatory state, including IL-1β overexpression by microglia cells, being causative of the cognitive impairment. These results highlight the pathological role for IL-33 in the central nervous system, independently of a specific neuropathological model.
Published: 2020
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40. Molecular basis of carrageenan-induced cytokines production in macrophages

Author: Rangel L. Silva, Aurélie Gombault, Bernardo S. Franklin, Isabelle Couillin, Fernando Q. Cunha, Francisco Isaac Fernandes Gomes, Alexandre Gomes de Macedo Maganin, Bernhard Ryffel, Norberto Peporine Lopes, Fernando Silva Ramalho, José C. Alves-Filho, Lucas Miranda Marques, Valérie F. J. Quesniaux, Lucas S. Ribeiro, Miriam D. Fonseca, Thiago M. Cunha, Dario S. Zamboni, Alexandre H. Lopes, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: Male, Inflammasomes, [SDV]Life Sciences [q-bio], Interleukin-1beta, lcsh:Medicine, Syk, INFLAMAÇÃO, Inflammation, Carrageenan, Biochemistry, Mice, 03 medical and health sciences, 0302 clinical medicine, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, lcsh:QH573-671, Colitis, Pannexin-1 channel, Molecular Biology, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Tumor Necrosis Factor-alpha, lcsh:Cytology, Chemistry, Research, Macrophages, lcsh:R, Inflammasome, Cell Biology, Macrophage Activation, medicine.disease, 3. Good health, Cell biology, Mice, Inbred C57BL, IL-1β, TRIF, Macrophages, Peritoneal, TLR4, Cytokines, Tumor necrosis factor alpha, NLRP3 Inflammasome, Signal transduction, medicine.symptom, 030217 neurology & neurosurgery, medicine.drug
Abstract: Background Low molecular weight carrageenan (Cg) is a seaweed-derived sulfated polysaccharide widely used as inflammatory stimulus in preclinical studies. However, the molecular mechanisms of Cg-induced inflammation are not fully elucidated. The present study aimed to investigate the molecular basis involved in Cg-induced macrophages activation and cytokines production. Methods Primary culture of mouse peritoneal macrophages were stimulated with Kappa Cg. The supernatant and cell lysate were used for ELISA, western blotting, immunofluorescence. Cg-induced mouse colitis was also developed. Results Here we show that Cg activates peritoneal macrophages to produce pro-inflammatory cytokines such as TNF and IL-1β. While Cg-induced TNF production/secretion depends on TLR4/MyD88 signaling, the production of pro-IL-1β relies on TLR4/TRIF/SYK/reactive oxygen species (ROS) signaling pathway. The maturation of pro-IL1β into IL-1β is dependent on canonical NLRP3 inflammasome activation via Pannexin-1/P2X7/K+ efflux signaling. In vivo, Cg-induced colitis was reduced in mice in the absence of NLRP3 inflammasome components. Conclusions In conclusion, we unravel a critical role of the NLRP3 inflammasome in Cg-induced pro-inflammatory cytokines production and colitis, which is an important discovery on the pro-inflammatory properties of this sulfated polysaccharide for pre-clinical studies. Graphical Abstract Carrageenan (Cg) is one the most used flogistic stimulus in preclinical studies. Nevertheless, the molecular basis of Cg-induced inflammation is not totally elucidated. Herein, Lopes et al. unraveled the molecular basis for Cg-induced macrophages production of biological active IL-1β. The Cg-stimulated macrophages produces pro-IL-1β depends on TLR4/TRIF/Syk/ROS, whereas its processing into mature IL-1β is dependent on the canonical NLRP3 inflammasome.
Published: 2020
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41. B-Cell Activating Factor Secreted by Neutrophils Is a Critical Player in Lung Inflammation to Cigarette Smoke Exposure

Author: Corinne Panek, Aurélie Gombault, Mégane Nascimento, Pascal Schneider, Nicolas Riteau, Marc Le Bert, Manon Bourinet, Bernhard Ryffel, Isabelle Couillin, Manoussa Fanny, F. Savigny, Valérie F. J. Quesniaux, Sarah Huot-Marchand, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: 0301 basic medicine, Male, Chemokine, Neutrophils, [SDV]Life Sciences [q-bio], B cell activating factor, cigarette smoke, mice, neutrophils, pulmonary inflammation, Gene Expression, Mice, 0302 clinical medicine, immune system diseases, B-Cell Activating Factor, Immunology and Allergy, Medicine, Macrophage, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Original Research, Inhalation Exposure, biology, Acquired immune system, 3. Good health, medicine.anatomical_structure, Neutrophil Infiltration, Cytokines, Disease Susceptibility, medicine.symptom, Inflammation Mediators, Bronchoalveolar Lavage Fluid, lcsh:Immunologic diseases. Allergy, Immunology, Inflammation, Respiratory Mucosa, Proinflammatory cytokine, 03 medical and health sciences, stomatognathic system, Tobacco Smoking, Animals, Humans, B-cell activating factor, Lung, Innate immune system, business.industry, Pneumonia, respiratory tract diseases, stomatognathic diseases, Disease Models, Animal, 030104 developmental biology, biology.protein, Tobacco Smoke Pollution, business, lcsh:RC581-607, 030215 immunology
Abstract: Cigarette smoke (CS) is the major cause of chronic lung injuries, such as chronic obstructive pulmonary disease (COPD). In patients with severe COPD, tertiary lymphoid follicles containing B lymphocytes and B cell-activating factor (BAFF) overexpression are associated with disease severity. In addition, BAFF promotes adaptive immunity in smokers and mice chronically exposed to CS. However, the role of BAFF in the early phase of innate immunity has never been investigated. We acutely exposed C57BL/6J mice to CS and show early BAFF expression in the bronchoalveolar space and lung tissue that correlates to airway neutrophil and macrophage influx. Immunostaining analysis revealed that neutrophils are the major source of BAFF. We confirmed in vitro that neutrophils secrete BAFF in response to cigarette smoke extract (CSE) stimulation. Antibody-mediated neutrophil depletion significantly dampens lung inflammation to CS exposure but only partially decreases BAFF expression in lung tissue and bronchoalveolar space suggesting additional sources of BAFF. Importantly, BAFF deficient mice displayed decreased airway neutrophil recruiting chemokines and neutrophil influx while the addition of exogenous BAFF significantly enhanced this CS-induced neutrophilic inflammation. This demonstrates that BAFF is a key proinflammatory cytokine and that innate immune cells in particular neutrophils, are an unconsidered source of BAFF in early stages of CS-induced innate immunity.
Published: 2020
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42. In addition to mTOR and JAK/STAT, NLRP3 inflammasome is another key pathway activated in sarcoidosis

Author: Riteau, Nicolas, Bernaudin, Jean-François, Huppertz, Christine, Jäger, Benedikt, Wieczorek, Grazyna, Engelhard, Peggy, Oliver, Stephen, Bauernfeind, Franz-Georg, Littlewood-Evans, Amanda, Welte, Tobias, Hornung, Veit, Prasse, Antje, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: Pulmonary and Respiratory Medicine, Granuloma, Sarcoidosis, integumentary system, business.industry, Inflammasomes, TOR Serine-Threonine Kinases, [SDV]Life Sciences [q-bio], JAK-STAT signaling pathway, Inflammasome, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, NLR Family, Pyrin Domain-Containing 3 Protein, Cancer research, Medicine, Humans, 030212 general & internal medicine, business, PI3K/AKT/mTOR pathway, medicine.drug
Abstract: International audience; The study of Huppertz and co-workers addresses the role of the NLRP3 inflammasome in sarcoidosis. Employing both mouse model and human samples, they provide evidence of NLPR3 inflammasome activation and increased IL-1β production in lung granulomas. http://bit.ly/32a4GsI Cite this article as: Riteau N, Bernaudin J-F. In addition to mTOR and JAK/STAT, NLRP3 inflammasome is another key pathway activated in sarcoidosis.
Published: 2020
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43. Ozone-Induced Aryl Hydrocarbon Receptor Activation Controls Lung Inflammation via Interleukin-22 Modulation

Author: Chloé Michaudel, Florent Bataille, Isabelle Maillet, Louis Fauconnier, Cyril Colas, Harry Sokol, Marjolène Straube, Aurélie Couturier-Maillard, Laure Dumoutier, Jacques van Snick, Valérie F. Quesniaux, Dieudonnée Togbe, Bernhard Ryffel, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), and Artimmune SAS
Subjects: CD4-Positive T-Lymphocytes, 0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], ILC3, Togbe D and Ryffel B (2020) Ozone-Induced Aryl Hydrocarbon Receptor Activation Controls Lung Inflammation via Interleukin-22 Modulation, Interleukin 22, Mice, Colas C, 0302 clinical medicine, Basic Helix-Loop-Helix Transcription Factors, IL-22, Immunology and Allergy, ComputingMilieux_MISCELLANEOUS, Original Research, Mice, Knockout, Quesniaux VF, Receptors, Interleukin-17, biology, Chemistry, Interleukin-17, Tryptophan, van Snick J, Lung Injury, Couturier-Maillard A, respiratory system, 3. Good health, Lipoxins, IL-17, Cytokine, medicine.anatomical_structure, Sokol H, Bataille F, Interleukin 17, Antibody, medicine.symptom, lcsh:Immunologic diseases. Allergy, Immunology, T cells, Inflammation, Dumoutier L, Lung injury, 03 medical and health sciences, Maillet I, Respiratory Hypersensitivity, medicine, Animals, Citation: Michaudel C, Straube M, Lung, Interleukins, AhR, Pneumonia, Aryl hydrocarbon receptor, Antibodies, Neutralizing, respiratory tract diseases, Mice, Inbred C57BL, ozone, 030104 developmental biology, Receptors, Aryl Hydrocarbon, Fauconnier L, inflammation, Cancer research, biology.protein, lcsh:RC581-607, 030215 immunology
Abstract: Airborne ozone exposure causes severe lung injury and inflammation. The aryl hydrocarbon Receptor (AhR) (1), activated in pollutant-induced inflammation, is critical for cytokine production, especially IL-22 and IL-17A. The role of AhR in ozone-induced lung inflammation is unknown. We report here that chronic ozone exposure activates AhR with increased tryptophan and lipoxin A4 production in mice. AhR−/− mice show increased lung inflammation, airway hyperresponsiveness, and tissue remodeling with an increased recruitment of IL-17A and IL-22-expressing cells in comparison to control mice. IL-17A- and IL-22-neutralizing antibodies attenuate lung inflammation in AhR−/− and control mice. Enhanced lung inflammation and recruitment of ILC3, ILC2, and T cells were observed after T cell-specific AhR depletion using the AhRCD4cre-deficient mice. Together, the data demonstrate that ozone exposure activates AhR, which controls lung inflammation, airway hyperresponsiveness, and tissue remodeling via the reduction of IL-22 expression.
Published: 2020
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44. Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens

Author: Normand, Sylvain, Waldschmitt, Nadine, Neerincx, Andreas, Martinez-Torres, Ruben Julio, Chauvin, Camille, Couturier-Maillard, Aurelie, Boulard, Olivier, Cobret, Laetitia, Awad, Fawaz, Huot, Ludovic, Ribeiro-Ribeiro, Andre, Lautz, Katja, Ruez, Richard, Delacre, Myriam, Bondu, Clovis, Guilliams, Martin, Scott, Charlotte, Segal, Anthony, Amselem, Serge, Hot, David, Karabina, Sonia, Bohn, Erwin, Ryffel, Bernhard, Poulin, Lionel F, Kufer, Thomas A, Chamaillard, Mathias, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), University of Cambridge [UK] (CAM), University College of London [London] (UCL), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Cologne, Universiteit Gent = Ghent University (UGENT), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO), University of Hohenheim, We thank Yvonne Postma for technical assistance., Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Technische Universität München [München] (TUM), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Trafic, Signalisation et Ciblage Intracellulaires, Institut Curie, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Unit of Immunoregulation and Mucosal Immunology [Ghent, Belgium], VIB Inflammation Research Center [Ghent, Belgium], UCL, Dept Med, Eberhard Karls Universität Tübingen, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universiteit Gent = Ghent University [Belgium] (UGENT), Gestionnaire, Hal Sorbonne Université, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), and UF de Génétique moléculaire [CHU Trousseau]
Subjects: Male, MONARCH-1, [SDV]Life Sciences [q-bio], Nod2 Signaling Adaptor Protein, ATG16L1, PROTEIN, MESH: Mice, Knockout, ACTIVATION, Mice, ATTENUATES COLON INFLAMMATION, MESH: Intracellular Signaling Peptides and Proteins/genetics, Medicine and Health Sciences, MESH: Animals, lcsh:Science, MESH: Inflammation/immunology, ComputingMilieux_MISCELLANEOUS, MESH: Enterobacteriaceae Infections/immunology, MESH: HSP90 Heat-Shock Proteins/metabolism, Mice, Knockout, CITROBACTER-RODENTIUM, Enterobacteriaceae Infections, Intracellular Signaling Peptides and Proteins, NF-kappa B, MESH: HEK293 Cells, MESH: Immune Tolerance/immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, SENSORS NOD1, MESH: NF-kappa B/metabolism, Acetylmuramyl-Alanyl-Isoglutamine, MESH: Citrobacter rodentium/immunology, MESH: Nod2 Signaling Adaptor Protein/metabolism, EXPRESSION, MESH: Intracellular Signaling Peptides and Proteins/metabolism, [SDV.IMM] Life Sciences [q-bio]/Immunology, Science, MESH: Acetylmuramyl-Alanyl-Isoglutamine/metabolism, DENDRITIC CELLS, Article, Cell Line, MESH: Bacterial Capsules/metabolism, Immune Tolerance, MESH: Enterobacteriaceae Infections/microbiology, Animals, Humans, HSP90 Heat-Shock Proteins, MESH: Mice, Bacterial Capsules, Inflammation, MESH: Humans, MUTATIONS, MESH: Gastrointestinal Microbiome/immunology, Ubiquitination, Biology and Life Sciences, MESH: Inflammation/microbiology, MESH: Male, Gastrointestinal Microbiome, MESH: Cell Line, HEK293 Cells, Citrobacter rodentium, MESH: Ubiquitination, lcsh:Q
Abstract: Mutations in the nucleotide-binding oligomerization domain protein 12 (NLRP12) cause recurrent episodes of serosal inflammation. Here we show that NLRP12 efficiently sequesters HSP90 and promotes K48-linked ubiquitination and degradation of NOD2 in response to bacterial muramyl dipeptide (MDP). This interaction is mediated by the linker-region proximal to the nucleotide-binding domain of NLRP12. Consequently, the disease-causing NLRP12 R284X mutation fails to repress MDP-induced NF-κB and subsequent activity of the JAK/STAT signaling pathway. While NLRP12 deficiency renders septic mice highly susceptible towards MDP, a sustained sensing of MDP through NOD2 is observed among monocytes lacking NLRP12. This loss of tolerance in monocytes results in greater colonization resistance towards Citrobacter rodentium. Our data show that this is a consequence of NOD2-dependent accumulation of inflammatory mononuclear cells that correlates with induction of interferon-stimulated genes. Our study unveils a relevant process of tolerance towards the gut microbiota that is exploited by an attaching/effacing enteric pathogen., Mutations in nucleotide-binding oligomerization domain protein 12 (NLRP12) are known to effect inflammatory processes. Here the authors show that NLRP12-mediated proteasomal degradation of NOD2 in monocytes promotes bacterial tolerance and colonisation in a model of enteric infection.
Published: 2018
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45. Functional and morphological differences of the lung upon acute and chronic ozone exposure in mice

Author: Yvon Julé, Louis Fauconnier, Bernhard Ryffel, Chloé Michaudel, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), and Artimmune SAS
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], lcsh:Medicine, Respiratory Mucosa, Lung injury, Article, Mice, 03 medical and health sciences, Ozone, Fibrosis, Respiratory Hypersensitivity, Toxicity Tests, Acute, Animals, Humans, Medicine, Respiratory system, Toxicity Tests, Chronic, lcsh:Science, Lung, ComputingMilieux_MISCELLANEOUS, Small Airway Remodeling, Air Pollutants, COPD, Multidisciplinary, business.industry, lcsh:R, Lung Injury, Pneumonia, respiratory system, medicine.disease, respiratory tract diseases, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, 13. Climate action, [SDV.IMM]Life Sciences [q-bio]/Immunology, Airway Remodeling, Respiratory epithelium, Female, Methacholine, lcsh:Q, business, medicine.drug
Abstract: Environmental air pollutants including ozone cause severe lung injury and aggravate respiratory diseases such as asthma and COPD. Here we compared the effect of ozone on respiratory epithelium injury, inflammation, hyperreactivity and airway remodeling in mice upon acute (1ppm, 1 h) and chronic exposure (1.5ppm, 2 h, twice weekly for 6 weeks). Acute ozone exposure caused respiratory epithelial disruption with protein leak and neutrophil recruitment in the broncho-alveolar space, leading to lung inflammation and airway hyperresponsiveness (AHR) to methacholine. All these parameters were increased upon chronic ozone exposure, including collagen deposition. The structure of the airways as assessed by automatic numerical image analysis showed significant differences: While acute ozone exposure increased bronchial and lumen circularity but decreased epithelial thickness and area, chronic ozone exposure revealed epithelial injury with reduced height, distended bronchioles, enlarged alveolar space and increased collagen deposition, indicative of peribronchiolar fibrosis and emphysema as characterized by a significant increase in the density and diameter of airspaces with decreased airspace numbers. In conclusion, morphometric numerical analysis enables an automatic and unbiased assessment of small airway remodeling. The structural changes of the small airways correlated with functional changes allowing to follow the progression from acute to chronic ozone induced respiratory pathology.
Published: 2018
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46. Gain of function mutation and inflammasome driven diseases in human and mouse models

Author: Mario D. Cordero, Bernhard Ryffel, Elísabet Alcocer-Gómez, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío [Sevilla], Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: 0301 basic medicine, Inflammasomes, [SDV]Life Sciences [q-bio], Interleukin-1beta, Immunology, Mutant, Anti-Inflammatory Agents, Autoimmunity, Inflammation, Proinflammatory cytokine, Pathogenesis, Mice, 03 medical and health sciences, 0302 clinical medicine, Animals, Humans, Immunology and Allergy, Medicine, Receptor, ComputingMilieux_MISCELLANEOUS, business.industry, Antibodies, Monoclonal, Receptors, Interleukin-1, Inflammasome, Autoinflammatory Syndrome, Cryopyrin-Associated Periodic Syndromes, 3. Good health, Disease Models, Animal, 030104 developmental biology, Gain of Function Mutation, Protein Multimerization, medicine.symptom, business, Inflammasome complex, 030217 neurology & neurosurgery, medicine.drug
Abstract: Activation of the NLRP3 inflammasome, a multiprotein complex, leading to caspase activation with production of proinflammatory IL-1β represents a major pathway of inflammation. Recent, studies in mice and human patients uncovered several gain-of- function (GOF) mutations in inflammasome sensor proteins that allow inflammasome assembly in the absence of cognate ligands to trigger autoinflammatory syndromes. Cryopyrin-associated periodic syndromes (CAPS) are rare autoinflammatory diseases, comprising a broad disease spectrum with varying severity. CAPS are associated with GOF mutations in the NLRP3 inflammasome and activation of IL-1ß leading to episodes of fever, cutaneous, musculoskeletal, articular, ocular, and neurological symptoms. Here, we review current knowledge on different mutations leading to CAPS and related clinical syndromes. Homologous gene mutations in mice provide insights into the regulation and consequences of the activation of different inflammasomes in several autoinflammatory syndrome. In view of the critical role of IL-1ß in the pathogenesis of autoinflammatory GOF mutations such as CAPS, blockade of the action of IL-1ß is critical. Therapeutic administration of recombinant IL-1 receptor antagonists or monoclonal anti-IL-1ß antibody had a beneficial effect. Furthermore, novel inhibitors of inflammasome complex formation such as MCC950 and related compounds attenuate experimental and clinical disease. The discovery of new GOF mutants of inflammasomes leading to further insights in pathomechanisms and the development of novel inhibitors represent a great challenge.
Published: 2018
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47. IL-33 signalling in liver immune cells enhances drug-induced liver injury and inflammation

Author: Brenda Naemi Nakagaki, Valérie F. J. Quesniaux, Débora Moreira Alvarenga, Bruna Araújo David, Bernhard Ryffel, José Carlos Farias Alves Filho, Ariane Barros Diniz, Renata Monti Rocha, Érika de Carvalho, Maria Alice Freitas Lopes, Pedro Marques, Gustavo B. Menezes, Rodrigo Guabiraba Brito, Sarah Cozzer Marchesi, Rafael M. Rezende, Alan Moreira de Araujo, Denise Carmona Cara, Rafaela Vaz Sousa Pereira, Maísa Mota Antunes, mmunopharmacology, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Laboratório de Imunobiofotônica, Departamento de Morfologia, Universidade Federal de Minas Gerais (UFMG), CNPq, CAPES, and FAPEMIG
Subjects: 0301 basic medicine, Chemokine, Neutrophils, [SDV]Life Sciences [q-bio], 0302 clinical medicine, Medicine, Bone Marrow Transplantation, Mice, Knockout, Liver injury, Mice, Inbred BALB C, biology, neutrophil, Analgesics, Non-Narcotic, 3. Good health, Liver, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Chemical and Drug Induced Liver Injury, medicine.symptom, Intravital microscopy, Signal Transduction, medicine.drug, acetaminophen overdose, Immunology, Inflammation, 03 medical and health sciences, Immune system, Animals, leucocyte, Acetaminophen, Pharmacology, DAMPs, business.industry, DNA, ST2, Interleukin-33, medicine.disease, Interleukin-1 Receptor-Like 1 Protein, Liver necrosis, Interleukin 33, 030104 developmental biology, IL-33, Hepatocytes, Cancer research, biology.protein, business, 030215 immunology
Abstract: International audience; The aim of this study was to investigate the contribution of IL-33/ST2 axis in the onset and progression of acute liver injury using a mice model of drug-induced liver injury (DILI). DILI was induced by overdose administration of acetaminophen (APAP) by oral gavage in wild-type BALB/c, ST2-deficient mice and in different bone marrow chimeras. Neutrophils were depleted by anti-Ly6G and macrophages with clodronate liposomes (CLL). Blood and liver were collected for biochemical, immunologic and genetic analyses. Mice were imaged by confocal intravital microscopy and liver non-parenchymal cells and hepatocytes were isolated for flow cytometry, genetic and immunofluorescence studies. Acetaminophen overdose caused a massive necrosis and accumulation of immune cells within the liver, concomitantly with IL-33 and chemokine release. Liver non-parenchymal cells were the major sensors for IL-33, and amongst them, neutrophils were the major players in amplification of the inflammatory response triggered by IL-33/ST2 signalling pathway. Blockage of IL-33/ST2 axis reduces APAP-mediated organ injury by dampening liver chemokine release and activation of resident and infiltrating liver non-parenchymal cells.
Published: 2017
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48. IL-17 suppresses the therapeutic activity of cancer vaccines through the inhibition of CD8 + T-cell responses

Author: Marine Oberkampf, Alexandre Tang, Eirik A Torheim, Pierre Rosenbaum, Gilles Dadaglio, Claude Leclerc, Francesc Rudilla, Catherine Fayolle, Isabelle Couillin, Couillin, Isabelle, Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Ligue Contre le Cancer, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), and Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]
Subjects: 0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Melanoma, Experimental, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Cancer Vaccines, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, Adjuvants, Immunologic, neutrophils, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunity, Neoplasms, Tumor immunity, medicine, Animals, Immunology and Allergy, Cytotoxic T cell, Th17 cells, RC254-282, Original Research, Chemistry, cytotoxic T cells, Interleukin-17, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunotherapy, Th1 Cells, RC581-607, 3. Good health, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], CTL, Cytolysis, IL-17, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Systemic administration, Cancer research, Female, Interleukin 17, Immunologic diseases. Allergy, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, CD8, Research Article
Abstract: International audience; Antitumor immunity is mediated by Th1 CD4+ and CD8+ T lymphocytes, which induce tumor-specific cytolysis, whereas Th17 CD4+ T cells have been described to promote tumor growth. Here, we explored the influence of IL-17 on the ability of therapeutic vaccines to induce the rejection of tumors in mice using several adjuvants known to elicit either Th1 or Th17-type immunity. Immunization of mice with Th1-adjuvanted vaccine induced high levels of IFN-γ-producing T cells, whereas injection with Th17-promoting adjuvants triggered the stimulation of both IL-17 and IFN-γ-producing T cells. However, despite their capacity to induce strong Th1 responses, these Th17-promoting adjuvants failed to induce the eradication of tumors. In addition, the systemic administration of IL-17A strongly decreases the therapeutic effect of Th1-adjuvanted vaccines in two different tumor models. This suppressive effect correlated with the capacity of systemically delivered IL-17A to inhibit the induction of CD8+ T-cell responses. The suppressive effect of IL-17A on the induction of CD8+ T-cell responses was abolished in mice depleted of neutrophils, clearly demonstrating the role played by these cells in the inhibitory effect of IL-17A in the induction of antitumor responses. These results demonstrate that even though strong Th1-type responses favor tumor control, the simultaneous activation of Th17 cells may redirect or curtail tumor-specific immunity through a mechanism involving neutrophils. This study establishes that IL-17 plays a detrimental role in the development of an effective antitumor T cell response and thus could strongly affect the efficiency of immunotherapy through the inhibition of CTL responses.
Published: 2020
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49. Klenkia terrae resistant to DNA extraction in germ-free mice stools illustrates the extraction pitfall faced by metagenomics

Author: Jean-Pierre Baudoin, Anthony Levasseur, Yusuke Ominami, Julien Andreani, Cecile Fremond, Matthieu Million, Saber Khelaifia, Jacques Yaacoub Bou Khalil, Didier Raoult, Bernard La Scola, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Hitachi, Ltd, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO)
Subjects: 0301 basic medicine, Fastidious organism, [SDV]Life Sciences [q-bio], 030106 microbiology, lcsh:Medicine, Real-Time Polymerase Chain Reaction, Article, Specimen Handling, Microbiology, Agar plate, Feces, Mice, 03 medical and health sciences, RNA, Ribosomal, 16S, Animals, lcsh:Science, Multidisciplinary, biology, lcsh:R, Bacteriology, 16S ribosomal RNA, Isolation (microbiology), biology.organism_classification, DNA extraction, Actinobacteria, RNA, Bacterial, 030104 developmental biology, Culturomics, Metagenomics, lcsh:Q, Bacteria
Abstract: Over the past decade, metagenomics has become the preferred method for exploring complex microbiota such as human gut microbiota. However, several bias affecting the results of microbiota composition, such as those due to DNA extraction, have been reported. These bias have been confirmed with the development of culturomics technique. In the present study, we report the contamination of a gnotobiotic mice unit with a bacterium first detected by gram staining. Scanning electron microscopy and transmission electron microscopy permitted to detect a bacterium with a thick cell wall. However, in parallel, the first attempt to identify and culture this bacterium by gene amplification and metagenomics of universal 16S rRNA failed. Finally, the isolation in culture of a fastidious bacterium not detected by using universal PCR was successfully achieved by using a BCYE agar plate with CO2 atmosphere at 30 °C. We performed genome sequencing of this bacterium using a strong extraction procedure. The genomic comparison allowed us to classify this bacterium as Klenkia terrae. And finally, it was also detected in the stool and kibble that caused the contamination by using specific qPCR against this bacterium. The elucidation of this contamination provides additional evidence that DNA extraction could be a bias for the study of the microbiota. Currently, most studies that strive to analyze and compare the gut microbiota are based on metagenomics. In a gnotobiotic mice unit contaminated with the fastidious Actinobacteria Klenkia terrae, standard culture, 16S rRNA gene amplification and metagenomics failed to identify the micro-organism observed in stools by gram-staining. Only a procedure based on culturomics allowed us to identify this bacterium and to elucidate the mode of contamination of the gnotobiotic mice unit through diet.
Published: 2020
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50. MEK5/ERK5 signaling mediates IL‐4‐induced M2 macrophage differentiation through regulation of c‐Myc expression

Author: André L. L. Saraiva, Emanuele Giurisato, Thiago M. Cunha, Marc LeBert, Priscilla Aparecida Tartari Pereira, Cathy Tournier, Douglas Silva Prado, Paula Ramos Viacava, Daniele C. Nascimento, Juliana E Toller-Kawahisa, João Paulo Mesquita Luiz, Fernando Q. Cunha, Bernhard Ryffel, José C. Alves-Filho, Valérie F. J. Quesniaux, Universidade de São Paulo (USP), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), and University of Manchester [Manchester]
Subjects: 0301 basic medicine, STAT3 Transcription Factor, Chemokine, MAP Kinase Signaling System, Immunology, Macrophage polarization, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MAP Kinase Kinase 5, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Mice, 0302 clinical medicine, Immunology and Allergy, Animals, M2 macrophages, STAT3, IMUNOLOGIA, Transcription factor, MEK5, Interleukin 4, Mitogen-Activated Protein Kinase 7, Mice, Knockout, Mice, Inbred BALB C, Manchester Cancer Research Centre, biology, ResearchInstitutes_Networks_Beacons/mcrc, Macrophages, IL-4, Cell Differentiation, Cell Biology, M2 Macrophage, Antigens, Differentiation, Cell biology, 030104 developmental biology, ERK5, Gene Expression Regulation, 030220 oncology & carcinogenesis, biology.protein, Phosphorylation, Interleukin-4, STAT6 Transcription Factor, CCL22
Abstract: International audience; Macrophages play a critical role in the regulation of immune responses. They are highly plastic cells, responding to diverse environmental stimuli to acquire different functional phenotypes. Intracellular signaling through mitogen-activated protein kinases (MAPKs) has been reported to regulate the differentiation of macrophages, but the role of the atypical MAPK ERK5 signaling in IL-4-mediated M2 macrophage differentiation is still unclear. Here, we showed that the ERK5 signaling pathway plays a critical role in IL-4-induced M2 macrophage differentiation. We found that pharmacological inhibition of MEK5, an immediate upstream activator of ERK5, with BIX markedly reduced the expression of classical M2 markers, such as Arg-1, Ym-1, and Fizz-1, as well as the production of M2-related chemokines and cytokines, CCL22, CCL17 and IGF-1 in IL-4-stimulated macrophages. Moreover, pharmacological inhibition of ERK5 with XMD8-92 also decreased the expression of several M2 markers induced by IL-4. In accordance, myeloid cell-specific Erk5 depletion (ERK5 ∆mye), using LysM cre /Erk5 f/f mice, confirmed the involvement of ERK5 signaling in IL-4-induced M2 polarization. Mechanistically, we found that pharmacological inhibition of ERK5 did not affect STAT6 phosphorylation, suggesting that ERK5 signaling regulates M2 differentiation in a STAT6-independent manner. However, we found that genetic deficiency or pharmacological inhibition of the MEK5/ERK5 pathway blocked the expression of c-Myc in IL-4-activated macrophages, which is a critical transcription factor involved in M2 differentiation. Taken together, our results reveal that activation of the MEK5/ERK5 signaling pathway is crucial in IL-4-induced M2 macrophage differentiation through the induction of c-Myc expression.
Published: 2020
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