Prdx4 limits caspase‐1 activation and restricts inflammasome‐mediated signaling by extracellular vesicles
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Authors
Lipinski, SimonePfeuffer, Steffen
Arnold, Philipp
Treitz, Christian
Aden, Konrad
Ebsen, Henriette
Falk‐Paulsen, Maren
Gisch, Nicolas
Fazio, Antonella
Kuiper, Jan
Luzius, Anne
Billmann‐Born, Susanne
Schreiber, Stefan
Nuñez, Gabriel
Beer, Hans‐Dietmar
Strowig, Till

Lamkanfi, Mohamed
Tholey, Andreas
Rosenstiel, Philip
Issue Date
2019-09-23
Metadata
Show full item recordAbstract
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 EVsCitation
EMBO J. 2019 Sep 23:e101266. doi: 10.15252/embj.2018101266.Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Publisher
EMBO PressJournal
The EMBO JournalPubMed ID
31544965Type
ArticleISSN
0261-41891460-2075
ae974a485f413a2113503eed53cd6c53
10.15252/embj.2018101266
Scopus Count
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International
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