| First Author | Lipinski S | Year | 2019 |
| Journal | EMBO J | Volume | 38 |
| Issue | 20 | Pages | e101266 |
| PubMed ID | 31544965 | Mgi Jnum | J:282239 |
| Mgi Id | MGI:6369888 | Doi | 10.15252/embj.2018101266 |
| Citation | Lipinski S, et al. (2019) Prdx4 limits caspase-1 activation and restricts inflammasome-mediated signaling by extracellular vesicles. EMBO J 38(20):e101266 |
| abstractText | Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active IL-1beta 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-1beta 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-DeltaLysMCre). 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-1beta-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. |
