TLR-stimulated IRAKM activates caspase-8 inflammasome in microglia and promotes neuroinflammation.
J Clin Invest
; 128(12): 5399-5412, 2018 12 03.
Article
em En
| MEDLINE
| ID: mdl-30372424
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-1ß release in microglia. Noncanonical inflammasome-derived IL-1ß 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-1ß via noncanonical caspase-8-dependent inflammasome is necessary for microglia to exert their pathogenic role during CNS inflammation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Microglia
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Encefalomielite Autoimune Experimental
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Caspase 8
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Quinases Associadas a Receptores de Interleucina-1
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Esclerose Múltipla
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China