A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis

作者：Laurie Baert, Mahdia Benkhoucha, Natalia Popa, Mashal Claude Ahmed, Benoît Manfroi, Jean Boutonnat, Nathalie Stürm, Gilda Raguénez, M. Tessier, Olivier Casez, Romain Marignier, Mitra Ahmadi, Alexis Broisat, Cathérine Ghezzi, Cyril Rivat, Corinne Sonrier, Michael Hahne, Dominique Baeten, Romain R. Vivès, Hugues Lortat‐Jacob, Patrice N. Marche, Pascal Schneider, Hans P. Lassmann, José Boucraut, Patrice H. Lalive, Bertrand Huard · 发表于：Annals of Neurology · 年份：2019 · DOI：10.1002/ana.25415 · 被引用次数：42 · 研究领域：Multiple Sclerosis Research Studies、Proteoglycans and glycosaminoglycans research、Immunotherapy and Immune Responses

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. INT...