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3 results on '"Joel T. Haas"'

1. Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis

Author

Marie Bobowski-Gerard, Clémence Boulet, Francesco P. Zummo, Julie Dubois-Chevalier, Céline Gheeraert, Mohamed Bou Saleh, Jean-Marc Strub, Amaury Farce, Maheul Ploton, Loïc Guille, Jimmy Vandel, Antonino Bongiovanni, Ninon Very, Eloïse Woitrain, Audrey Deprince, Fanny Lalloyer, Eric Bauge, Lise Ferri, Line-Carolle Ntandja-Wandji, Alexia K. Cotte, Corinne Grangette, Emmanuelle Vallez, Sarah Cianférani, Violeta Raverdy, Robert Caiazzo, Viviane Gnemmi, Emmanuelle Leteurtre, Benoit Pourcet, Réjane Paumelle, Kim Ravnskjaer, Guillaume Lassailly, Joel T. Haas, Philippe Mathurin, François Pattou, Laurent Dubuquoy, Bart Staels, Philippe Lefebvre, Jérôme Eeckhoute, Université de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU de Lille), ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016), ANR-16-IDEX-0004,ULNE,ULNE(2016), ANR-21-CE14-0032,HSCreg,Identification et caractérisation d'un nouveau facteur de transcription controlant l'activation des cellules stellaires et la fibrose hépatique(2021), ANR-20-CE14-0034,DeCodeNASH,L'activation métabolique des cellules dendritiques dans la steatopathie métabolique(2020), and ANR-21-CE17-0016,MEdicAL,Cibler les MEcanismes cellulaires du défaut de régénération pour le développement d'une médecine de précision pour l'hépatite ALcoolique.(2021)

Subjects
DNA-Binding Proteins, Liver Cirrhosis, Mice, Multidisciplinary, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Animals, Humans, General Chemistry, Genomics, Myofibroblasts, General Biochemistry, Genetics and Molecular Biology, Transcription Factors
Abstract

Tissue injury triggers activation of mesenchymal lineage cells into wound-repairing myofibroblasts, whose unrestrained activity leads to fibrosis. Although this process is largely controlled at the transcriptional level, whether the main transcription factors involved have all been identified has remained elusive. Here, we report multi-omics analyses unraveling Basonuclin 2 (BNC2) as a myofibroblast identity transcription factor. Using liver fibrosis as a model for in-depth investigations, we first show that BNC2 expression is induced in both mouse and human fibrotic livers from different etiologies and decreases upon human liver fibrosis regression. Importantly, we found that BNC2 transcriptional induction is a specific feature of myofibroblastic activation in fibrotic tissues. Mechanistically, BNC2 expression and activities allow to integrate pro-fibrotic stimuli, including TGFβ and Hippo/YAP1 signaling, towards induction of matrisome genes such as those encoding type I collagen. As a consequence, Bnc2 deficiency blunts collagen deposition in livers of mice fed a fibrogenic diet. Additionally, our work establishes BNC2 as potentially druggable since we identified the thalidomide derivative CC-885 as a BNC2 inhibitor. Altogether, we propose that BNC2 is a transcription factor involved in canonical pathways driving myofibroblastic activation in fibrosis.

Published
2022
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2. Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Author

Maria P. Longhi, Jörg Cammenga, Kamil R. Kranc, Samuel Pic, David Dombrowicz, Benoit Viollet, Olivier Molendi-Coste, Arnaud Villacreces, C. Becquart, Alexandra M. Bogomolova, Peter Carmeliet, Steve Lancel, Jean-Sébastien Annicotte, Christophe Paget, Joel T. Haas, Cédric Dewas, Julien Wartelle, Simon Tavernier, Luciana Berod, Nabil Rabhi, Seiichi Oyadomari, Laurent Pineau, Milica Vukovic, Bart Staels, Céline Gheeraert, Guillemette Marot, Laurent L'homme, Ezra Aksoy, Sébastien Fleury, Sandrine Quemener, Sophie Janssens, Matthieu Levavasseur, Alexis C. Boulter, Hélène Dehondt, Marc Foretz, Delphine Staumont-Sallé, Talia Velasco-Hernandez, Artemii Nikitin, Denis A. Mogilenko, Aurelie Melchior, 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), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), 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), Tokushima University, Linköping University (LIU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Queen Mary University of London (QMUL), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), MOdel for Data Analysis and Learning (MODAL), Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Paul Painlevé - UMR 8524 (LPP), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille)-Université de Lille, Sciences et Technologies, The University of Florida College of Medicine, Universiteit Gent = Ghent University [Belgium] (UGENT), Helmholtz Centre for Infection Research (HZI), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Laboratoire Paul Painlevé - UMR 8524 (LPP), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-École polytechnique universitaire de Lille (Polytech Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-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)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Recherche Biomédicale des Armées (IRBA), Departement de Physiologie, Faculté de Médecine, EA4484, IFR 114 IMPRT, Université de Lille, Droit et Santé, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), 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)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fujii Memorial Institute of Medical Sciences [Tokushima, Japan] (Institute of Advanced Medical Sciences), Department of Hematology [Linköping, Sweden] (Institute for Clinical and Experimental Medicine), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre for Haemato-Oncology [London, UK] (Barts Cancer Institute), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, Santé publique : épidémiologie et qualité des soins-EA 2694 (CERIM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, University of Florida College of Medicine [Gainesville, FL, USA], Hannover Medical School [Hannover] (MHH), The William Harvey Research Institute [London, UK] (NIHR Barts Biomedical Research Centre), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100, Institut National de la Santé et de la Recherche Médicale (INSERM), ER Stress and Inflammation [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], and Centre for Biochemical Pharmacology [London, UK] (William Harvey Research Institute)

Subjects
X-Box Binding Protein 1, XBP1, [SDV]Life Sciences [q-bio], Citric Acid Cycle, Inflammation, UPR, Biology, fatty acids, General Biochemistry, Genetics and Molecular Biology, Mice, chemistry.chemical_compound, 03 medical and health sciences, Immune system, 0302 clinical medicine, IL-23, medicine, Animals, metabolic reprogramming, dendritic cells, innate immunity, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Mice, Knockout, Hexokinase, 0303 health sciences, Innate immune system, mtROS, hexokinase, Toll-Like Receptors, Dendritic cell, psoriasis, glycolysis, Acquired immune system, Immunity, Innate, Mitochondria, Cell biology, Cellular Microenvironment, chemistry, 030220 oncology & carcinogenesis, Unfolded Protein Response, Unfolded protein response, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Reactive Oxygen Species, 030217 neurology & neurosurgery
Abstract

International audience; Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

Published
2019
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3. Title: Bile acid alterations in non-alcoholic fatty liver disease, obesity, insulin resistance and type 2 diabetes: what do the human studies tell?

Author

Bart Staels, Anne Tailleux, Joel T. Haas, Guillaume Grzych, Oscar Chávez-Talavera, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), 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), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Derudas, Marie-Hélène, and Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], education, Type 2 diabetes, 030204 cardiovascular system & hematology, digestive system, Bile Acids and Salts, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Non-alcoholic Fatty Liver Disease, Internal medicine, Diabetes mellitus, Nonalcoholic fatty liver disease, Genetics, medicine, Humans, Obesity, Molecular Biology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Nutrition and Dietetics, Human studies, Bile acid, business.industry, nutritional and metabolic diseases, Cell Biology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Bile acid metabolism, Insulin Resistance, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

The purpose of this review is to discuss the influence of obesity, insulin resistance, type 2 diabetes (T2D), and nonalcoholic fatty liver disease (NAFLD) on bile acid metabolism and to analyze whether these findings reinforce current beliefs about the role of bile acids in the pathophysiology of these diseases.Discordant results on plasma bile acid alterations in NAFLD patients have been reported. Obesity, insulin resistance, and T2D, common comorbidities of NAFLD, have been associated with bile acid changes, but the individual bile acid species variations differ between studies (summarized in this review), perhaps because of clinicobiological differences between the studied patient populations and the heterogeneity of statistical analyses applied.The regulatory role of bile acids in metabolic and cellular homeostasis renders bile acids attractive candidates as players in the pathophysiology of NAFLD. However, considering the complex relationship between NAFLD, obesity, insulin resistance and T2D, it is difficult to establish clear and independent associations between bile acid alterations and these individual diseases. Though bile acid alterations may not drive NAFLD progression, signaling pathways activated by bile acids remain potent therapeutic targets for its treatment. Further studies with appropriate matching or adjustment for potential confounding factors are necessary to determine which pathophysiological conditions drive the alterations in bile acid metabolism.

Published
2019
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