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

• Published in: The EMBO journal Vol. 38; no. 20; pp. e101266 - n/a
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.10.2019; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Activation; Animals; Caspase; Caspase 1 - genetics; Caspase 1 - metabolism; caspase‐1; Cell interactions; Clonal deletion; Cysteine; Cytokines - metabolism; Deactivation; EMBO19; extracellular vesicle; Extracellular vesicles; Extracellular Vesicles - metabolism; Female; IL‐1β; Immune response; Inactivation; inflammasome; Inflammasomes; Inflammasomes - immunology; Inflammasomes - metabolism; Inflammation; Inflammatory response; Lipopolysaccharides; Lipopolysaccharides - toxicity; Macrophages; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid cells; Peroxidase; Peroxiredoxin; Peroxiredoxins - physiology; Prdx4; Proteolysis; Sepsis; Septic shock; Shock, Septic - chemically induced; Shock, Septic - immunology; Shock, Septic - pathology; Shock, Septic - prevention & control; Signal Transduction; Vesicles; IL‐1β; Prdx4; caspase‐1; extracellular vesicle; inflammasome; IL-1β; caspase-1
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2018101266

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. Graphical Abstract The thiol‐specific peroxidase Prdx4 directly regulates caspase‐1 activity in a redox‐sensitive manner to control IL‐1β maturation.