B cell-specific METTL3 depletion exacerbates experimental autoimmune encephalomyelitis.

N6-methyladenosine (m6A), the most prevalent RNA modification, plays a pivotal role in regulating mRNA metabolism and cellular processes such as immune responses. Although the m6A methyltransferase METTL3 is known to regulate T-cell homeostasis and influence experimental autoimmune encephalomyelitis (EAE, a model for multiple sclerosis (MS)), its function within B cells remains poorly defined. Crucially, we observed that METTL3 expression is significantly downregulated in peripheral blood mononuclear cells (PBMCs) from MS patients and within B cells isolated from EAE mice. To directly investigate the functional consequences of this B-cell-specific METTL3 reduction in neuroinflammation, we generated B cell-specific METTL3 knockout mice (Mettl3flox/floxCD19Cre). Strikingly, this targeted deletion of METTL3 in B cells markedly exacerbated EAE severity, demonstrated by significantly worsened clinical disease scores, increased spinal cord inflammation, and greater demyelination. Further mechanistic dissection revealed how B-cell METTL3 deficiency drives this exacerbated pathology: it promoted B cell apoptosis, inhibited the differentiation of regulatory B cell (Breg) subpopulations, increased the proportion of pro-inflammatory iNOS+ macrophages, and elevated the production of IL-6, BAFF, and BCMA. In the central nervous system, it promotes neurological damage by affecting axonal function and facilitating the loss of neurons. Collectively, these findings demonstrate that METTL3 functions as a critical negative regulator within B cells, restraining their contribution to neuroinflammation in the EAE model. Importantly, therapeutically relevant overexpression of METTL3 specifically in B cells significantly reduced both the clinical severity and incidence of EAE, underscoring its potential as a novel therapeutic target for MS and similar autoimmune disorders involving pathogenic B-cell responses.