Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of clinical investigation, 2018-12, Vol.128 (12), p.5399-5412

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.