Prdx4 limits caspaseâ 1 activation and restricts inflammasomeâ mediated signaling by extracellular vesicles
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
2019-10-15
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Citation
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 (2019). "Prdx4 limits caspaseâ 1 activation and restricts inflammasomeâ mediated signaling by extracellular vesicles." The EMBO Journal 38(20): n/a-n/a.
Abstract
Inflammasomes are cytosolic protein complexes, which orchestrate the maturation of active ILâ 1β by proteolytic cleavage via caspaseâ 1. Although many principles of inflammasome activation have been described, mechanisms that limit inflammasomeâ dependent immune responses remain poorly defined. Here, we show that the thiolâ specific peroxidase peroxiredoxinâ 4 (Prdx4) directly regulates ILâ 1β generation by interfering with caspaseâ 1 activity. We demonstrate that caspaseâ 1 and Prdx4 form a redoxâ sensitive regulatory complex via caspaseâ 1 cysteine 397 that leads to caspaseâ 1 sequestration and inactivation. Mice lacking Prdx4 show an increased susceptibility to LPSâ induced septic shock. This effect was phenocopied in mice carrying a conditional deletion of Prdx4 in the myeloid lineage (Prdx4â Î LysMCre). Strikingly, we demonstrate that Prdx4 coâ localizes with inflammasome components in extracellular vesicles (EVs) from inflammasomeâ activated macrophages. Purified EVs are able to transmit a robust ILâ 1βâ dependent inflammatory response in vitro and also in recipient mice in vivo. Loss of Prdx4 boosts the proâ inflammatory potential of EVs. These findings identify Prdx4 as a critical regulator of inflammasome activity and provide new insights into remote cellâ toâ cell communication function of inflammasomes via macrophageâ derived EVs.SynopsisThis study shows that the thiolâ specific peroxidase peroxiredoxinâ 4 (Prdx4) directly regulates ILâ 1β generation by interfering with inflammasome activity. Prdx4 forms a redoxâ sensitive regulatory complex with the caspaseâ 1 at the cysteine in position 397 that leads to caspaseâ 1 sequestration and inactivation.Lack of Prdx4 in myeloid cells leads to elevated ILâ 1β levels and increased clinical symptoms in a murine septic shock model.Prdx4 interacts with caspaseâ 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 ILâ 1βâ dependent inflammatory response in vitro and in vivo.Loss of Prdx4 leads to an increased proâ inflammatory potential of EVs, indicating a potential role of Prdx4 in the regulation of cellâ toâ cell communication via macrophageâ derived EVs.The thiolâ specific peroxidase Prdx4 directly regulates caspaseâ 1 activity in a redoxâ sensitive manner to control ILâ 1β maturation.Publisher
Wiley Periodicals, Inc.
ISSN
0261-4189 1460-2075
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