Journal
CELL HOST & MICROBE
Volume 24, Issue 1, Pages 97-+Publisher
CELL PRESS
DOI: 10.1016/j.chom.2018.05.009
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Funding
- US NIH [R01GM115366, R01CA160417, R01AT005076, R01GM063075, R01GM044100, R01GM050441]
- Natural Science Foundation of Guangdong Province [2016A030308011]
- American Cancer Society [RSG-16-014-01-CDD]
- National Natural Science Foundation of China [31671435, 81400132, 81772508]
- Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme
- Lin He's Academician Workstation of New Medicine and Clinical Translation
- International Scientific and Technology Cooperation Program of China [2015DFA31490]
- Ligue contre le Cancer Comite de Charente-Maritime
- Agence National de la Recherche (ANR) - Projets blancs
- ANR
- ERA-Net for Research on Rare Diseases
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Chancelerie des universites de Paris (Legs Poix)
- Fondation pour la Recherche Medicale (FRM)
- European Commission
- European Research Council (ERC)
- Fondation Carrefour
- Institut National du Cancer (INCa)
- Inserm (HTE)
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere
- Searave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- [P30CA047904]
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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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