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5 results on '"Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université (Nantes Univ)"'

1. Selective Targeting of IL-15Rα Is Sufficient to Reduce Inflammation

Author

Meghnem, Dihia, Maillasson, Mike, Barbieux, Isabelle, Morisseau, Sébastien, Keita, Dalloba, Jacques, Yannick, Quéméner, Agnès, Mortier, Erwan, Mortier, Erwan, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Structure fédérative de recherche François Bonamy (Nantes Univ - SFR François Bonamy), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université (Nantes Univ), and Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Inflammation, Interleukin-15, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.IMM] Life Sciences [q-bio]/Immunology, interleukin, receptor, IL-2, Immunology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, inhibition, Killer Cells, Natural, Mice, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Interleukin-15 Receptor alpha Subunit, homeostasis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Animals, Cytokines, Immunology and Allergy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy
Abstract

International audience; Cytokines are crucial molecules for maintaining the proper functioning of the immune system. Nevertheless, a dysregulation of cytokine expression could be involved in the pathogenesis of autoimmune diseases. Interleukin (IL)-15 is a key factor for natural killer cells (NK) and CD8 T cells homeostasis, necessary to fight cancer and infections but could also be considered as a pro-inflammatory cytokine involved in autoimmune inflammatory disease, including rheumatoid arthritis, psoriasis, along with tumor necrosis factor alpha (TNF-a), IL-6, and IL-1b. The molecular mechanisms by which IL-15 exerts its inflammatory function in these diseases are still unclear. In this study, we generated an IL-15-derived molecule called NANTIL-15 (New ANTagonist of IL-15), designed to selectively inhibit the action of IL-15 through the high-affinity trimeric IL-15Ra/IL-2Rb/gc receptor while leaving IL-15 signaling through the dimeric IL-2Rb/gc receptor unaffected. Administrating of NANTIL-15 in healthy mice did not affect the IL-15-dependent cell populations such as NK and CD8 T cells. In contrast, we found that NANTIL-15 efficiently reduced signs of inflammation in a collagen-induced arthritis model. These observations demonstrate that the inflammatory properties of IL-15 are linked to its action through the trimeric IL-15Ra/IL-2Rb/gc receptor, highlighting the interest of selectively targeting this receptor.

Published
2022

2. Altered epithelial barrier functions in the colon of patients with spina bifida

Author

Charlène Brochard, Guillaume Bouguen, Raphael Olivier, Tony Durand, Sébastien Henno, Benoît Peyronnet, Mael Pagenault, Chloé Lefèvre, Gaëlle Boudry, Mikael Croyal, Alain Fautrel, Maxime Esvan, Alain Ropert, Anne Dariel, Laurent Siproudhis, Michel Neunlist, CHU Pontchaillou [Rennes], The Enteric Nervous System in gut and brain disorders [U1235] (TENS), 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), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre référence maladies rares Spina Bifida, Service des Maladies de l'Appareil Digestif [CHU Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service d'anatomopathologie [Rennes], Hôpital Pontchaillou, Service d'urologie [Rennes] = Urology [Rennes], Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Mass Spectrometry Core Facility [Nantes] (CRNH-O ), Structure fédérative de recherche François Bonamy (Nantes Univ - SFR François Bonamy), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université (Nantes Univ), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Marseille, and Bernard, Emilie

Subjects
Adult, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Colon, Rectum, Colonoscopy, Coleoptera, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Surveys and Questionnaires, Animals, Humans, Spinal Dysraphism, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Our objectives were to better characterize the colorectal function of patients with Spina Bifida (SB). Patients with SB and healthy volunteers (HVs) completed prospectively a standardized questionnaire, clinical evaluation, rectal barostat, colonoscopy with biopsies and faecal collection. The data from 36 adults with SB (age: 38.8 [34.1–47.2]) were compared with those of 16 HVs (age: 39.0 [31.0–46.5]). Compared to HVs, rectal compliance was lower in patients with SB (p = 0.01), whereas rectal tone was higher (p = 0.0015). Ex vivo paracellular permeability was increased in patients with SB (p = 0.0008) and inversely correlated with rectal compliance (r = − 0.563, p = 0.002). The expression of key tight junction proteins and inflammatory markers was comparable between SB and HVs, except for an increase in Claudin-1 immunoreactivity (p = 0.04) in SB compared to HVs. TGFβ1 and GDNF mRNAs were expressed at higher levels in patients with SB (p = 0.02 and p = 0.008). The levels of acetate, propionate and butyrate in faecal samples were reduced (p = 0.04, p = 0.01, and p = 0.02, respectively). Our findings provide evidence that anorectal and epithelial functions are altered in patients with SB. The alterations in these key functions might represent new therapeutic targets, in particular using microbiota-derived approaches.Clinical Trials: NCT02440984 and NCT03054415.

Published
2022

3. PiT2 deficiency prevents increase of bone marrow adipose tissue during skeletal maturation but not in OVX-induced osteoporosis

Author

Frangi, Giulia, Guicheteau, Marie, Jacquot, Frederic, Pyka, Grzegorz, Kerckhofs, Greet, Feyeux, Magalie, Veziers, Joëlle, Guihard, Pierre, Halgand, Boris, Sourice, Sophie, Guicheux, Jérôme, Prieur, Xavier, Beck, Laurent, Beck-Cormier, Sarah, Beck, Laurent, Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR Odontologie, Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Structure fédérative de recherche François Bonamy (Nantes Univ - SFR François Bonamy), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université (Nantes Univ), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Université Catholique de Louvain = Catholic University of Louvain (UCL), Technologie campus Gent - KU Leuven (KU Leuven), Santé - François Bonamy, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), UCL - SST/IMMC/MEED - Mechatronic, Electrical Energy, and Dynamics Systems, and UCL - SSS/IREC - Institut de recherche expérimentale et clinique

Subjects
EXPRESSION, SLC20A1, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Endocrinology, Diabetes and Metabolism, adipocytes, PiT2/Slc20a2, post-menopausal osteoporotic mouse model, bone, Mice, Endocrinology & Metabolism, Endocrinology, Bone Marrow, Bone Density, ABLATION, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, SERUM PHOSPHATE, Slc20a2, Science & Technology, marrow, Diabetes and Metabolism, MODEL, Bone Diseases, Metabolic, MICE, Adipose Tissue, OBESITY, PiT2, Osteoporosis, Female, MINERAL DENSITY, Life Sciences & Biomedicine, RESTRICTION
Abstract

The common cellular origin between bone marrow adipocytes (BMAds) and osteoblasts contributes to the intimate link between bone marrow adipose tissue (BMAT) and skeletal health. An imbalance between the differentiation ability of BMSCs towards one of the two lineages occurs in conditions like aging or osteoporosis, where bone mass is decreased. Recently, we showed that the sodium-phosphate co-transporter PiT2/SLC20A2 is an important determinant for bone mineralization, strength and quality. Since bone mass is reduced in homozygous mutant mice, we investigated in this study whether the BMAT was also affected in PiT2-/- mice by assessing the effect of the absence of PiT2 on BMAT volume between 3 and 16 weeks, as well as in an ovariectomy-induced bone loss model. Here we show that the absence of PiT2 in juveniles leads to an increase in the BMAT that does not originate from an increased adipogenic differentiation of bone marrow stromal cells. We show that although PiT2-/- mice have higher BMAT volume than control PiT2+/+ mice at 3 weeks of age, BMAT volume do not increase from 3 to 16 weeks of age, leading to a lower BMAT volume in 16-week-old PiT2-/- compared to PiT2+/+ mice. In contrast, the absence of PiT2 does not prevent the increase in BMAT volume in a model of ovariectomy-induced bone loss. Our data identify SLC20a2/PiT2 as a novel gene essential for the maintenance of the BMAd pool in adult mice, involving mechanisms of action that remain to be elucidated, but which appear to be independent of the balance between osteoblastic and adipogenic differentiation of BMSCs.

Published
2022

4. Effects of proprotein convertase subtilisin kexin type 9 modulation in human pancreatic beta cells function

Author

Matthieu Wargny, Valentin Blanchard, Mikaël Croyal, Valery Gmyr, E. Nobecourt, Stéphane Ramin-Mangata, Cécile Vindis, Bertrand Cariou, Mathieu Armanet, Gilles Lambert, Stéphanie Billon-Crossouard, Nicolas Diotel, Olivier Meilhac, François Pattou, Philippe Hulin, Aurélie Thedrez, Cédric Le May, Brice Nativel, Audrey Aguesse, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de La Réunion (UR), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Nantes (UN)-Université de Nantes (UN)-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), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Université Paris Diderot - Paris 7 (UPD7), Recherche translationnelle sur le diabète - U 1190 (RTD), 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), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Nutrition Humaine Ouest (CRNH Ouest), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut du Thorax [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), Structure fédérative de recherche François Bonamy (Nantes Univ - SFR François Bonamy), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université (Nantes Univ), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), 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), and CHU Lille

Subjects
0301 basic medicine, medicine.medical_specialty, Diabetes risk, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Flow cytometry, PCSK9, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Insulin-Secreting Cells, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Secretion, Subtilisins, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, Chemistry, Statins, LDL receptor, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Proprotein convertase, Beta cell, 030104 developmental biology, Endocrinology, Receptors, LDL, PCSK9 inhibitors, Kexin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine
Abstract

International audience; Background and aims: Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) is an endogenous inhibitor of the LDL receptor (LDLR). Mendelian randomization studies suggest that PCSK9 deficiency increases diabetes risk, but the underlying mechanisms remain unknown. The aim of our study was to investigate whether PCSK9 or its inhibition may modulate beta cell function.Methods: We assessed PCSK9 and insulin colocalization in human pancreatic sections by epifluorescent and confocal microscopy. We also investigated the expression and the function of PCSK9 in the human EndoC-8H1 beta cell line, by ELISA and flow cytometry, respectively. PCSK9 was inhibited with Alirocumab or siRNA. LDLR expression and LDL uptake were assessed by flow cytometry.Results: PCSK9 was expressed and secreted from beta cells isolated from human pancreas as well as from EndoC-8H1 cells. PCSK9 secretion was enhanced by statin treatment. Recombinant PCSK9 decreased LDLR abundance at the surface of these cells, an effect abrogated by Alirocumab. Alirocumab as well as PCSK9 silencing increased LDLR expression at the surface of EndoC-8H1 cells. Neither exogenous PCSK9, nor Alirocumab, nor PCSK9 silencing significantly altered glucose-stimulated insulin secretion (GSIS) from these cells. High-low density lipoproteins (LDL) concentrations decreased GSIS, but the addition of PCSK9 or its inhibition did not modulate this phenomenon.Conclusions: While PCSK9 regulates LDLR abundance in beta cells, inhibition of exogenous or endogenous PCSK9 does not appear to significantly impact insulin secretion. This is reassuring for the safety of PCSK9 inhibitors in terms of beta cell function.

Published
2021

5. Generation of three human induced pluripotent stem cell lines with IRX5 knockout and knockin genetic editions using CRISPR-Cas9 system

Author

Robin Canac, Amandine Caillaud, Bastien Cimarosti, Aurore Girardeau, Hanan Hamamy, Bruno Reversade, Carine Bonnard, Zeina R. Al Sayed, Laurent David, Jeremie Poschmann, Patricia Lemarchand, Guillaume Lamirault, Nathalie Gaborit, Center for Reproductive Medicine, Reversade, Bruno, Canac, Robin, Caillaud, Amandine, Cimarosti, Bastien, Girardeau, Aurore, Hamamy, Hanan, Bonnard, Carine, Al Sayed, Zeina R., David, Laurent, Poschmann, Jeremie, Lemarchand, Patricia, Lamirault, Guillaume, Gaborit, Nathalie, School of Medicine, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Genève = University of Geneva (UNIGE), Genome Institute of Singapore (GIS), Amsterdam UMC - Amsterdam University Medical Center, Agency for science, technology and research [Singapore] (A*STAR), Structure fédérative de recherche François Bonamy (Nantes Univ - SFR François Bonamy), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université (Nantes Univ), 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), and gaborit, nathalie

Subjects
Homeodomain Proteins, Heterozygote, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, QH301-705.5, Homozygote, Induced Pluripotent Stem Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cell Biology, General Medicine, Homeobox genes, Transcription Factor, Liver cell carcinoma, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Genetics, cardiovascular system, Animals, Humans, Myocytes, Cardiac, Biology (General), CRISPR-Cas Systems, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Transcription Factors, Developmental Biology
Abstract

Studies on animal models have shown that Irx5 is an important regulator of cardiac development and that it regulates ventricular electrical repolarization gradient in the adult heart. Mutations in IRX5 have also been linked in humans to cardiac conduction defects. In order to fully characterize the role of IRX5 during cardiac development and in cardiomyocyte function, we generated three genetically-modified human induced pluripotent stem cell lines: two knockout lines (heterozygous and homozygous) and a knockin HA-tagged line (homozygous)., French National Research Agency; La Fédération Française de Cardiologie; Fondation Lefoulon-Delalande; Marie Curie Inter-national Incoming Fellowship FP7-PEOPLE-2012-IIF; Marion Elizabeth Brancher (MEB)

Published
2022

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