Journal
EMBO JOURNAL
Volume 38, Issue 20, Pages -Publisher
WILEY
DOI: 10.15252/embj.2018101266
Keywords
caspase-1; extracellular vesicle; IL-1 beta; inflammasome; Prdx4
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [EXC306, EXC2167]
- Bundesministerium fur Bildung und Forschung (BMBF) E: med consortium SysInflame [012X1306F]
- SH Excellence Chair Program
- Helmholtz Association [VH-NG-933]
- DFG [STR 1343/1]
- [CRC1182]
- [CRC877]
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Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL-1 beta 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-1 beta 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-Delta LysMCre). 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-1 beta-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.
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