Prdx4 limits caspase-1 activation and restricts inflammasome-mediated signaling by extracellular vesicles.
Animals
Caspase 1
/ genetics
Cytokines
/ metabolism
Extracellular Vesicles
/ metabolism
Female
Inflammasomes
/ immunology
Lipopolysaccharides
/ toxicity
Macrophages
/ immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Peroxiredoxins
/ physiology
Shock, Septic
/ chemically induced
Signal Transduction
IL-1β
Prdx4
caspase-1
extracellular vesicle
inflammasome
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
15 10 2019
15 10 2019
Historique:
received:
29
11
2018
revised:
05
08
2019
accepted:
21
08
2019
pubmed:
24
9
2019
medline:
7
1
2020
entrez:
24
9
2019
Statut:
ppublish
Résumé
Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL-1β 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-1β 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-1β-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.
Identifiants
pubmed: 31544965
doi: 10.15252/embj.2018101266
pmc: PMC6792017
doi:
Substances chimiques
Cytokines
0
Inflammasomes
0
Lipopolysaccharides
0
Peroxiredoxins
EC 1.11.1.15
Prdx4 protein, mouse
EC 1.11.1.15
Casp1 protein, mouse
EC 3.4.22.36
Caspase 1
EC 3.4.22.36
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e101266Subventions
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : EXC306
Pays : International
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : EXC2167
Pays : International
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : CRC1182
Pays : International
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : CRC877
Pays : International
Organisme : Bundesministerium für Bildung und Forschung (BMBF)
ID : 012X1306F
Pays : International
Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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