Prdx4 limits caspase-1 activation and restricts inflammasome-mediated signaling by extracellular vesicles.
EMBO J
; 38(20): e101266, 2019 10 15.
Article
em En
| MEDLINE
| ID: mdl-31544965
ABSTRACT
Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL-1ß by proteolytic cleavage via caspase-1. Although many principles of inflammasome activation have been described, mechanisms that limit inflammasome-dependent immune responses remain poorly defined. Here, we show that the thiol-specific peroxidase peroxiredoxin-4 (Prdx4) directly regulates IL-1ß generation by interfering with caspase-1 activity. We demonstrate that caspase-1 and Prdx4 form a redox-sensitive regulatory complex via caspase-1 cysteine 397 that leads to caspase-1 sequestration and inactivation. Mice lacking Prdx4 show an increased susceptibility to LPS-induced septic shock. This effect was phenocopied in mice carrying a conditional deletion of Prdx4 in the myeloid lineage (Prdx4-ΔLysMCre). Strikingly, we demonstrate that Prdx4 co-localizes with inflammasome components in extracellular vesicles (EVs) from inflammasome-activated macrophages. Purified EVs are able to transmit a robust IL-1ß-dependent inflammatory response in vitro and also in recipient mice in vivo. Loss of Prdx4 boosts the pro-inflammatory potential of EVs. These findings identify Prdx4 as a critical regulator of inflammasome activity and provide new insights into remote cell-to-cell communication function of inflammasomes via macrophage-derived EVs.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Choque Séptico
/
Caspase 1
/
Peroxirredoxinas
/
Inflamassomos
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Vesículas Extracelulares
/
Macrófagos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Alemanha