Unknown

Dataset Information

0

Prdx4 limits caspase-1 activation and restricts inflammasome-mediated signaling by extracellular vesicles


ABSTRACT: Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL 1b 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 1b 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-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 1b-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 insights into remote cell-to-cell communication function of inflammasomes via macrophage-derived EVs.

SUBMITTER: Dr. Simone Lipinski 

PROVIDER: S-SCDT-EMBOJ-2018-101266 | biostudies-other |

REPOSITORIES: biostudies-other

Similar Datasets

| S-EPMC6792017 | biostudies-literature
| S-EPMC2657210 | biostudies-literature
| S-EPMC8432597 | biostudies-literature
| S-EPMC8767097 | biostudies-literature
| S-EPMC3683568 | biostudies-literature
| S-EPMC7022218 | biostudies-literature
| S-EPMC4285429 | biostudies-literature
| S-EPMC3340363 | biostudies-literature
| S-EPMC4761285 | biostudies-literature
| S-EPMC3926011 | biostudies-literature