| Summary: | Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here, we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and serves as a pivotal mediator of microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and, thereby, promotes recruitment of T cells into the central nervous system. Peli1-deficient mice are refractory to EAE induction despite their competent production of inflammatory T cells in the peripheral lymphoid organs. Notably, Peli1 regulates a novel signaling axis of the toll-like receptor pathway that mediates degradation of Traf3, a potent inhibitor of MAP kinase activation and gene induction. Ablation of Traf3 restores the microglial activation and EAE sensitivity of Peli1-deficient mice. These findings establish Peli1 as a microglia-specific mediator of autoimmune neuroinflammation and suggest a novel signaling mechanism of Peli1 function.
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