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TLR-stimulated IRAKM activates caspase-8 inflammasome in microglia and promotes neuroinflammation
Cun-Jin Zhang, … , Richard M. Ransohoff, Xiaoxia Li
Cun-Jin Zhang, … , Richard M. Ransohoff, Xiaoxia Li
Published October 29, 2018
Citation Information: J Clin Invest. 2018;128(12):5399-5412. https://doi.org/10.1172/JCI121901.
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Research Article Autoimmunity Inflammation

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

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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.

Authors

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

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Figure 7

Microglia-intrinsic IRAKM–caspase-8 inflammasome activation is required for neutrophil recruitment and T cell expansion in the CNS.

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Microglia-intrinsic IRAKM–caspase-8 inflammasome activation is required ...
(A) Microglia were isolated from brains of EAE mice with indicated genotypes at peak disease and cultured for 24 hours. The supernatant was analyzed by ELISA for cytokine and chemokine production. (B–D) Flow cytometry analysis of microglia (B), IL-17+CD4+, IFN-γ+CD4+ cell (C) and neutrophil (D) in brains of EAE mice with indicated genotypes at different time points after active immunization with MOG35–55. (E) IL-17+CD4+, IFN-γ+CD4+ cells, and neutrophil in brains of mice indicated in Figure 6F were analyzed by flow cytometry. Data are representative of 2 independent experiments (n = 4/group). Mean ± SEM. *P < 0.05, **P < 0.01 (unpaired 2-tailed Student’s t test).
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