Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Autoimmunity Inflammation

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

  • Text
  • PDF
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

×

Figure 1

Microglia-specific ASC deficiency attenuated EAE disease.

Options: View larger image (or click on image) Download as PowerPoint
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.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts