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TLR-stimulated IRAKM activates caspase-8 inflammasome in microglia and promotes neuroinflammation

Zhang, CJ;Jiang, M;Zhou, H;Liu, W;Wang, C;Kang, Z;Han, B;Zhang, Q;Chen, X;Xiao, J;Fisher, A;Kaiser, WJ;Murayama, MA;Iwakura, Y;Gao, J;Carman, J;Dongre, A;Dubyak, G;Abbott, DW;Shi, FD;Ransohoff, RM;Li, X;

NLRP3 inflammasome plays a critical spatiotemporal role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). This study reports a mechanistic insight into noncanonical NLRP3 inflammasome activation in microglia for the effector stage of EAE. Microglia-specific deficiency of ASC (apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment [CARD] domain) attenuated T cell expansion and neutrophil recruitment during EAE pathogenesis. Mechanistically, TLR stimulation led to IRAKM-caspase-8-ASC complex formation, resulting in the activation of caspase-8 and IL-1 release in microglia. Noncanonical inflammasome-derived IL-1 produced by microglia in the CNS helped to expand the microglia population in an autocrine manner and amplified the production of inflammatory cytokines/chemokines. Furthermore, active caspase-8 was markedly increased in the microglia in the brain tissue from patients with multiple sclerosis. Taken together, our study suggests that microglia-derived IL-1 via noncanonical caspase-8-dependent inflammasome is necessary for microglia to exert their pathogenic role during CNS inflammation.