Targeting extracellular matrix components to attenuate microglia neuroinflammation: A study of fibulin-2 and CSPGs in a model of multiple sclerosis

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^-/- mice and the CSPG-synthesis inhibitor difluorosamine (DIF), respectively, enhanced recovery of disability and reduced neuroinflammation in EAE mice. However, their combined targeting did not result in additive therapeutic effects beyond either alone. This study underscores the complex regulatory roles of ECM components on neuroinflammation and provides insights into potential therapeutic strategies for neuroinflammatory diseases.