Matrix metalloprotease-9 modulates microglial/macrophage responses in murine brain demyelination.

Multiple sclerosis (MS) is a chronic autoimmune disorder, in which the immune system targets the protective myelin sheath surrounding axons in the brain, spinal cord and optic nerve, leading to demyelination and ultimately neurodegeneration. Promoting remyelination to delay or halt disease progression remains a major therapeutic challenge in MS research. Matrix metalloproteases (MMPs) have been implicated in the pathogenesis of MS. Elevated levels of MMP-9 have been detected in cerebrospinal fluid (CSF), serum and demyelinating lesions of MS patients, where MMP-9 contributes to myelin breakdown, epitope generation, and leukocyte infiltration. In the in vivo experimental autoimmune encephalomyelitis and lysophosphatidylcholine (LPC) murine MS models, Mmp9-/- mice exhibited delayed resolution of disease symptoms, suggesting a role for MMP-9 in remyelination. In this study, we investigated the role of MMP-9 in demyelination and remyelination, using two complementary models: LPC-induced demyelination in ex vivo brain slices and cuprizone (CPZ)-induced demyelination in vivo. In LPC-treated slices, MMP-9 deficiency impaired remyelination via microglia/macrophage-mediated mechanisms. Consistently, Mmp9-/- mice displayed increased numbers of activated microglia/macrophages in the corpus callosum following CPZ intoxication, with modest persistence during remyelination compared to WT mice. Naïve Mmp9-/- microglia/macrophages also showed enhanced myelin debris phagocytosis compared to WT cells. However, MMP-9 deficiency had minimal impact on demyelination or remyelination in the CPZ model. Proteomic analysis of CSF revealed differential expression of inflammatory mediators, including decreased levels of CCL2 and CXCL9, whereas CCL20 was increased in Mmp9-/- CPZ-treated mice. Collectively, these findings indicate that MMP-9 does not directly regulate demyelination and remyelination in the CPZ-induced demyelination model, but increases microglial abundance, highlighting its indirect role in CNS demyelination.