Laurie Baert1, Mahdia Benkhoucha2, Natalia Popa3, Mashal C Ahmed1, Benoit Manfroi1, Jean Boutonnat4, Nathalie Sturm4, Gilda Raguenez3, Marine Tessier3, Olivier Casez5, Romain Marignier6, Mitra Ahmadi7, Alexis Broisat7, Catherine Ghezzi7, Cyril Rivat8, Corinne Sonrier8, Michael Hahne9, Dominique Baeten10,11, Romain R Vives12, Hugues Lortat-Jacob12, Patrice N Marche1, Pascal Schneider13, Hans P Lassmann14, Jose Boucraut3, Patrice H Lalive2,15, Bertrand Huard1. 1. Institute for Advanced Biosciences, Grenoble Alpes University/National Institute of Health and Medical Research U1209/National Center for Scientific Research UMR5309, La Tronche, France. 2. Department of Pathology and Immunology, School of Medicine, University of Geneva, Geneva, Switzerland. 3. CRN2M, National Center for Scientific Research UMR6231, Medicine Faculty, Mediterranean University, Marseille, France. 4. Department of Anatomopathology and Cytology, University Hospital, Grenoble, France. 5. Department of Neurology, University Hospital, Grenoble, France. 6. Neuroinflammation and Neuro-Oncology Team, Faculty of Medicine Laennec, Lyon Neurosciences Research Center, Lyon, France. 7. Bioclinical Radiopharmaceuticals, National Institute of Health and Medical Research U1309, Grenoble, France. 8. Neurosciences Institute, National Institute of Health and Medical Research U1051, Montpellier, France. 9. Institute for Molecular Genetics, National Center for Scientific Research UMR5535, Montpellier, France. 10. Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, the Netherlands. 11. Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 12. Institute of Structural Biology, Grenoble Alpes University, UMR5075, National Center for Scientific Research, Grenoble, France. 13. Department of Biochemistry, University of Lausanne, Épalinges, Switzerland. 14. Center for Brain Research, Medical University of Vienna, Vienna, Austria. 15. Department of Neurosciences, Division of Neurology, Geneva University Hospital, Switzerland.
Abstract
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.
OBJECTIVE: The two related tumornecrosis 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.
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