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

CJ Zhang, M Jiang, H Zhou, W Liu… - The Journal of …, 2018 - Am Soc Clin Investig
CJ Zhang, M Jiang, H Zhou, W Liu, C Wang, Z Kang, B Han, Q Zhang, X Chen, J Xiao…
The Journal of clinical investigation, 2018Am Soc Clin Investig
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 …
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-1β release in microglia. Noncanonical inflammasome-derived IL-1β 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-1β via noncanonical caspase-8–dependent inflammasome is necessary for microglia to exert their pathogenic role during CNS inflammation.
The Journal of Clinical Investigation