Cigarette smoke inhibits the NLRP3 inflammasome and leads to caspase-1 activation via the TLR4-TRIF-caspase-8 axis in human macrophages.
FASEB J
; 34(1): 1819-1832, 2020 01.
Article
em En
| MEDLINE
| ID: mdl-31914643
ABSTRACT
The NLRP3 inflammasome is formed by the sensor NLRP3, the adaptor ASC, and pro-caspase-1. Assembly and activation of the inflammasome trigger caspase-1-dependent cleavage of pro-IL-1ß and pro-IL-18 into their secreted forms. Cigarette smoke is a risk factor for chronic inflammatory diseases and is associated with macrophage dysfunction. The impact of cigarette smoke on NLRP3-dependent responses in macrophages is largely unknown. Herein, we investigated the effects of cigarette smoke extract (CSE) on the NLRP3 inflammasome in human monocyte-derived macrophages (MDMs) and THP-1 cells stimulated with lipopolysaccharide (LPS) and LPS plus the NLRP3 inflammasome activator ATP. We found that CSE inhibited the release of IL-1ß and IL-18 as well as the expression of NLRP3 acting mainly at the transcriptional level. Interestingly, we found that CSE increased the caspase-1 activity via an NLRP3-independent and TLR4-TRIF-caspase-8-dependent pathway. Activation of caspase-1 by CSE led to a reduction of the basal glycolytic flux and impaired glycolytic burst in response to LPS. Overall, our findings unveil novel pathways leading to immune-metabolic alterations in human macrophages exposed to cigarette smoke. These mechanisms may contribute to macrophage dysfunction and increased risk of infection in smokers.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fumaça
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Transdução de Sinais
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Caspase 1
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Inflamassomos
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Proteína 3 que Contém Domínio de Pirina da Família NLR
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Macrófagos
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article