1. A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis
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Mahdia Benkhoucha, Mashal Claude Ahmed, Dominique Baeten, Romain Marignier, Jose Boucraut, Olivier Casez, Michael Hahne, Jean Boutonnat, Corinne Sonrier, Benoit Manfroi, Laurie Baert, Patrice N. Marche, Nathalie Sturm, Marine Tessier, Patrice H. Lalive, Romain R. Vivès, Bertrand Huard, Cyril Rivat, Catherine Ghezzi, Hans Lassmann, Pascal Schneider, Natalia Popa, Gilda Raguenez, Alexis Broisat, Hugues Lortat-Jacob, Mitra Ahmadi, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Department of Clinical Immunology and Rheumatology [Academic Medical Center, Amsterdam], University of Amsterdam [Amsterdam] (UvA), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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)-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)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry [Lausanne], Université de Lausanne (UNIL), University of Vienna [Vienna], Department of Clinical Neurosciences [Geneva, Switzerland], Unit of Neuroimmunology and Neuromuscular Diseases [Geneva, Switzerland] (Division of Neurology), Geneva University Hospitals - HUG [Switzerland]-Geneva University Hospitals - HUG [Switzerland], This work was supported by Grenoble Alpes University (B.H.), the National Institute of Health and Medical Research (B.H.), the Association for Aid to Multiple Sclerosis Research (B.H.), the National Agency for Research (program center of excellence in neurodegeneration obtained within the Grenoble excellence in neurodegeneration network, B.H.), the Swiss National Science Foundation (310030_156961/310030_176256 to PS and 310030_153164/310030_176678 to PL), and the Swiss Multiple Sclerosis Society (P.L.)., Clinical Immunology and Rheumatology, AII - Inflammatory diseases, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Lausanne = University of Lausanne (UNIL), Grenoble Alpes University, the National Institute of Health and Medical Research, the Association for Aid to Multiple Sclerosis Research), the National Agency for Research (program center of excellence in neurodegeneration obtained within the Grenoble excellence in neurodegeneration network, the Swiss National Science Foundation (310030_156961/310030_176256 to PS and 310030_153164/310030_176678 )The Swiss Multiple Sclerosis Society, and MARCHE, Patrice
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Male ,0301 basic medicine ,T-Lymphocytes ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,B-Cell Activating Factor ,Medicine ,Mice, Knockout ,Reverse Transcriptase Polymerase Chain Reaction ,Chondroitin Sulfates ,Middle Aged ,Immunohistochemistry ,Interleukin-10 ,3. Good health ,Interleukin 10 ,Neurology ,Adult ,Aged ,Animals ,Astrocytes/immunology ,Astrocytes/metabolism ,Astrocytes/pathology ,B-Cell Activating Factor/metabolism ,Cell Proliferation ,Chondroitin Sulfate Proteoglycans/metabolism ,Chondroitin Sulfates/metabolism ,Cytokines/immunology ,Disease Models, Animal ,Encephalomyelitis, Autoimmune, Experimental/immunology ,Encephalomyelitis, Autoimmune, Experimental/metabolism ,Encephalomyelitis, Autoimmune, Experimental/pathology ,Female ,Humans ,Interleukin-10/immunology ,Macrophages/pathology ,Multiple Sclerosis/immunology ,Multiple Sclerosis/metabolism ,Multiple Sclerosis/pathology ,T-Lymphocytes/immunology ,Tumor Necrosis Factor Ligand Superfamily Member 13/genetics ,Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism ,Tumor Necrosis Factor Ligand Superfamily Member 13/pharmacology ,Cytokines ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Tumor necrosis factor alpha ,medicine.symptom ,Encephalomyelitis, Autoimmune, Experimental ,Multiple Sclerosis ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Tumor Necrosis Factor Ligand Superfamily Member 13 ,Inflammation ,03 medical and health sciences ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,B-cell activating factor ,Autoimmune encephalitis ,business.industry ,Macrophages ,Multiple sclerosis ,medicine.disease ,030104 developmental biology ,Chondroitin Sulfate Proteoglycans ,chemistry ,Chondroitin sulfate proteoglycan ,Astrocytes ,Immunology ,Cytokine secretion ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
International audience; OBJECTIVE:The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.METHODS:APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.RESULTS:APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.INTERPRETATION:Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.© 2019 American Neurological Association.
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- 2019