The two related TNF members APRIL and BAFF are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to an effective biological response with the depletion of B cells, but it was associated to an unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here we show that APRIL expression is induced in CNS lesions from experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and APRIL absence worsens the disease. Accordingly, lesions from MS patients also showed induction of APRIL expression with a subset of infiltrating macrophages producing APRIL, as in peripheral tissues. Notably, all the APRIL secreted by these macrophages specifically accumulated in reactive astrocytes present in lesions. APRIL is a factor binding to heparan sulfate proteoglycans (HSPGs). APRIL bound also to chondroitin sulfate proteoglycans (CSPG), and the upregulation of CSPG of type E in reactive astrocytes explained the latter selective accumulation. Astrocytes responded to APRIL by producing sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Taken together, our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF.