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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 December 3, 2018; First published October 29, 2018
Citation Information: J Clin Invest. 2018;128(12):5399-5412. https://doi.org/10.1172/JCI121901.
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Categories: 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 1

Microglia-specific ASC deficiency attenuated EAE disease.

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Microglia-specific ASC deficiency attenuated EAE disease.
Analysis of re...
Analysis of results for WT→ASCfl/+Cx3cr1Cre-ER (ASCΔWT) and WT→ASCfl/flCx3cr1Cre-ER (ASCΔmicroglia) bone marrow chimera mice in EAE disease. (A) FACS analysis of CreER-EYFP expression in microglia of ASCΔWT mice with or without tamoxifen administration on day 16 of EAE induced by active immunization with MOG35–55. (B) Mean clinical score for EAE in ASCΔWT (n = 6) and ASCΔmicroglia (n = 5) bone marrow chimera mice induced by active immunization with MOG35–55. Absolute numbers (C) and gating strategy (D) of immune cell infiltration determined at the peak of disease in brains of EAE mice by flow cytometry (n = 3/group). (E) Inflammatory gene expression in the lumbar spinal cords as assessed at the peak of disease (n = 4). (F) Luxol Fast Blue and H&E staining of lumbar spinal cords harvested at the peak of disease. Scale bars: 200 μm. (G and H) Mean clinical score for EAE in ASCΔWT and ASCΔmicroglia bone marrow chimera mice induced by adoptive Th17 (G) (n = 7 and n = 5, respectively) or (H) Th1 (n = 5/group) transfer. 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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