Prdx4 limits caspase‐1 activation and restricts inflammasome‐mediated signaling by extracellular vesicles. (23rd September 2019)

• Record Type: Journal Article
• Authors: Lipinski, Simone; Pfeuffer, 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
• Is Part Of: EMBO journal. Volume 38:Number 20(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-09-23
• Subjects: caspase‐1 -- extracellular vesicle -- IL‐1β -- inflammasome -- Prdx4; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2018101266
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: This study shows that the thiol‐specific peroxidase peroxiredoxin‐4 (Prdx4) directly regulates IL‐1β generation by interfering with inflammasome activity. Prdx4 forms a redox‐sensitive regulatory complex with the caspase‐1 at the cysteine in position 397 that leads to caspase‐1 sequestration and inactivation. Lack of Prdx4 in myeloid cells leads to elevated IL‐1β levels and increased clinical symptoms in a murine septic shock model. Prdx4 interacts with caspase‐1 in the cytosolic compartment and in extracellular vesicles (EVs) of activated macrophages. Purified EVs from macrophages contain all components of the NLRP3 inflammasome as well as Prdx4 and are able to convey a robust IL‐1β‐dependent inflammatory response in vitro and in vivo . Loss of Prdx4 leads to an increased pro‐inflammatory potential of EVs, indicating a potential role of Prdx4 in the regulation of cell‐to‐cell communication via macrophage‐derived EVs. Abstract : The thiol‐specific peroxidase Prdx4 directly regulates caspase‐1 activity in a redox‐sensitive manner to control IL‐1β maturation.