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

Cun Jin Zhang, Meiling Jiang, Hao Zhou, Weiwei Liu, Chenhui Wang, Zizhen Kang, Bing Han, Quanri Zhang, Xing Chen, Jianxin Xiao, Amanda Fisher, William Kaiser, Masanori A. Murayama, Yoichiro Iwakura, Ji Gao, Julie Carman, Ashok Dongre, George Dubyak, Derek W. Abbott, Fu Dong ShiRichard M. Ransohoff, Xiaoxia Li

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5399-5412
Number of pages14
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhang, C. J., Jiang, M., Zhou, H., Liu, W., Wang, C., Kang, Z., Han, B., Zhang, Q., Chen, X., Xiao, J., Fisher, A., Kaiser, W., Murayama, M. A., Iwakura, Y., Gao, J., Carman, J., Dongre, A., Dubyak, G., Abbott, D. W., ... Li, X. (2018). TLR-stimulated IRAKM activates caspase-8 inflammasome in microglia and promotes neuroinflammation. Journal of Clinical Investigation, 128(12), 5399-5412. https://doi.org/10.1172/JCI121901