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

• Simone Lipinski ^[4] ; Steffen Pfeuffer ^[4] ; Philipp Arnold ^[5] ; Christian Treitz ^[1] ; Konrad Aden ^[6] ; Henriette Ebsen ^[4] ; Maren Falk‐Paulsen ^[4] ; Nicolas Gisch ^[7] ; Antonella Fazio ^[4] ; Jan Kuiper ^[4] ; Anne Luzius ^[4] ; Susanne Billmann‐Born ^[4] ; Stefan Schreiber ^[8] ; Gabriel Nuñez ^[2] ; Hans‐Dietmar Beer ^[9] ; Till Strowig ^[10] ; Mohamed Lamkanfi ^[3] ; Andreas Tholey ^[1] ; Philip Rosenstiel ^[4]
  1. [1] Max Planck Institute for Experimental Medicine

     Max Planck Institute for Experimental Medicine

     Landkreis Göttingen, Alemania

     
  2. [2] University of Michigan–Ann Arbor

     University of Michigan–Ann Arbor

     City of Ann Arbor, Estados Unidos

     
  3. [3] Ghent University

     Ghent University

     Arrondissement Gent, Bélgica

     
  4. [4] 1 Institute of Clinical Molecular Biology Christian‐Albrechts‐University and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  5. [5] 2 Anatomical Institute Christian‐Albrechts‐University of Kiel Kiel Germany
  6. [6] 1 Institute of Clinical Molecular Biology Christian‐Albrechts‐University and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany; 4 1st Department of Internal Medicine University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  7. [7] 5 Division of Bioanalytical Chemistry, Priority Area Infections Research Center Borstel, Leibniz Lung Center Borstel Germany
  8. [8] 4 1st Department of Internal Medicine University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  9. [9] 7 Department of Dermatology University Hospital Zurich Zurich Switzerland; 8 Faculty of Medicine University of Zurich Zurich Switzerland
  10. [10] 9 Department of Microbial Immune Regulation Helmholtz Centre for Infection Research Braunschweig Germany

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 20, 2019
• Idioma: inglés
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• Resumen

  • 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.