4.7 Article

Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

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CELL HOST & MICROBE
卷 24, 期 1, 页码 97-+

出版社

CELL PRESS
DOI: 10.1016/j.chom.2018.05.009

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资金

  1. US NIH [R01GM115366, R01CA160417, R01AT005076, R01GM063075, R01GM044100, R01GM050441]
  2. Natural Science Foundation of Guangdong Province [2016A030308011]
  3. American Cancer Society [RSG-16-014-01-CDD]
  4. National Natural Science Foundation of China [31671435, 81400132, 81772508]
  5. Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme
  6. Lin He's Academician Workstation of New Medicine and Clinical Translation
  7. International Scientific and Technology Cooperation Program of China [2015DFA31490]
  8. Ligue contre le Cancer Comite de Charente-Maritime
  9. Agence National de la Recherche (ANR) - Projets blancs
  10. ANR
  11. ERA-Net for Research on Rare Diseases
  12. Association pour la recherche sur le cancer (ARC)
  13. Canceropole Ile-de-France
  14. Chancelerie des universites de Paris (Legs Poix)
  15. Fondation pour la Recherche Medicale (FRM)
  16. European Commission
  17. European Research Council (ERC)
  18. Fondation Carrefour
  19. Institut National du Cancer (INCa)
  20. Inserm (HTE)
  21. Institut Universitaire de France
  22. LeDucq Foundation
  23. LabEx Immuno-Oncology
  24. RHU Torino Lumiere
  25. Searave Foundation
  26. SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
  27. SIRIC Cancer Research and Personalized Medicine (CARPEM)
  28. Paris Alliance of Cancer Research Institutes (PACRI)
  29. [P30CA047904]

向作者/读者索取更多资源

Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage. The resultant N-terminal GSDMD fragments then trigger macrophage pyroptotic cell death in a phospholipase C gamma 1 (PLCG1)dependent fashion. Administration of the antioxidant vitamin E that reduces lipid peroxidation, chemical inhibition of PLCG1, or genetic Caspase-11 deletion or Gsdmd inactivation prevents polymicrobial sepsis in Gpx4(-/)-mice. Collectively, this study suggests that lipid peroxidation drives GSDMD-mediated pyroptosis and hence constitutes a potential therapeutic target for lethal infection.

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