The extracellular matrix (ECM) plays an important role in the central nervous system (CNS), shaping tissue structure and functions as well as contributing to the pathology of chronic diseases such as multiple sclerosis (MS). ECM components, including fibulin-2 (FBLN2) and chondroitin sulfate proteoglycans (CSPGs), may impact neuroinflammation and remyelination. We investigated the capacity of FBLN2 to modulate immune responses and evaluated its interaction with CSPGs in experimental autoimmune encephalomyelitis (EAE), a common model for MS. We show that FBLN2 deficiency in EAE mice reduced microglial pro-inflammatory activity, while effects on monocyte-derived macrophages and border-associated macrophages were less pronounced. Targeting FBLN2 and CSPGs individually, using FBLN2