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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 6

Microglia-intrinsic caspase-8 inflammasome activation is required for microglia survival and proliferation in the CNS.

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Microglia-intrinsic caspase-8 inflammasome activation is required for mi...
(A) The proliferation of microglia from WT EAE mouse brain at peak disease was analyzed by flow cytometry after staining with antibodies against CD45, CD11b, IL-1R, Ki67, and caspase-8–FLICA. (B) Primary microglia isolated from mouse brain with indicated genotypes were stimulated with LPS+ATP in the presence of IL-1Rα followed by PI staining and flow cytometry analysis (n = 3). (C and D) Spinal cord from EAE mice with indicated genotypes at peak disease were stained with antibodies against caspase-8–FLICA, Ki67, and Brdu. EYFP indicates the microglia (n = 6/group). WT→Cx3cr1Cre-ER (Cx3Cr1ΔWT). Scale bars, 50 μm. (E) Flow cytometry analysis of Ki67+ microglia in brains of EAE mice with indicated genotypes (n = 6). (F–J) WT and Il1b–/– microglia isolated from adult mouse brain were transferred to Csf1rfl/flCx3cr1cre mice after the fourth tamoxifen injection (5 mg/mouse/week, i.p.) and the mice were subjected to EAE induction 2 weeks after the last tamoxifen injection (n = 6). Clinical score was presented as mean ± SEM (F). Total microglia (G) and Ki67+ microglia (H) in brains at EAE peak were analyzed by flow cytometry. Brdu+ microglia were analyzed in brain slices (I and J). Scale bar, 50 μm. Data are representative of 2 independent experiments; mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 (unpaired 2-tailed Student’s t test). EAE clinical score by 2-way ANOVA.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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