Myeloid ZNRF1 suppresses autoimmune demyelination and neuroinflammation by regulating MHC-II-mediated T cell activation.

Multiple sclerosis (MS) is an autoimmune and neuroinflammation disease characterized by axonal damage, inflammatory demyelination, and neurodegeneration. However, the precise mechanisms underlying MS pathogenesis remain largely unclear. Here, we identify ZNRF1, an E3 ubiquitin ligase, as a critical regulator of experimental autoimmune encephalomyelitis (EAE), a murine model that recapitulates the autoimmune demyelination features of MS. Mice lacking ZNRF1 exhibit increased susceptibility to EAE progression. Notably, ZNRF1 depletion in peripheral myeloid cells, but not in microglia, leads to enhanced immune cell infiltration into the central nervous system, resulting in demyelination and exacerbated disease severity. The heightened EAE severity in Znrf1-deficient mice is associated with increased polarization of Th1 and Th17 cells, elevated antigen-specific T helper cell proliferation, and amplified immune responses. Furthermore, following EAE induction, macrophages from Znrf1-deficient mice display elevated surface expression of MHC class II (MHC-II) molecules. Collectively, our findings suggest that ZNRF1 in peripheral myeloid cells plays a suppressive role in neuroinflammation by regulating MHC-II surface expression, thereby controlling antigen-specific T-cell proliferation and activation.