@article{03c0e5d2c5c145e3a164f28552fe8fc5,
title = "Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis",
abstract = "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.",
keywords = "GPX4, GSDMD, caspase-11, ferroptosis, immunometabolism, inflammasome, lipid peroxidation, pyroptosis, sepsis",
author = "Rui Kang and Ling Zeng and Shan Zhu and Yangchun Xie and Jiao Liu and Qirong Wen and Lizhi Cao and Min Xie and Qitao Ran and Guido Kroemer and Haichao Wang and Billiar, {Timothy R.} and Jianxin Jiang and Daolin Tang",
note = "Funding Information: We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US NIH (R01GM115366, R01CA160417, R01AT005076, R01GM063075, R01GM044100, and R01GM050441), the Natural Science Foundation of Guangdong Province (2016A030308011), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD), the National Natural Science Foundation of China (31671435, 81400132, and 81772508), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017), Lin He's Academician Workstation of New Medicine and Clinical Translation (2017), and the International Scientific and Technology Cooperation Program of China (2015DFA31490). This project partly utilized University of Pittsburgh Cancer Institute shared resources supported by award P30CA047904. G.K. is supported by the Ligue contre le Cancer Comit{\'e} de Charente-Maritime ({\'e}quipe labelis{\'e}e); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Canc{\'e}rop{\^o}le {\^I}le-de-France; Chancelerie des universit{\'e}s de Paris (Legs Poix), Fondation pour la Recherche M{\'e}dicale (FRM); the European Commission; the European Research Council (ERC); Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumi{\`e}re, the Searave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). Funding Information: We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US NIH ( R01GM115366 , R01CA160417 , R01AT005076 , R01GM063075 , R01GM044100 , and R01GM050441 ), the Natural Science Foundation of Guangdong Province ( 2016A030308011 ), the American Cancer Society ( Research Scholar Grant RSG- 16-014-01-CDD ), the National Natural Science Foundation of China ( 31671435 , 81400132 , and 81772508 ), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017), Lin He's Academician Workstation of New Medicine and Clinical Translation (2017), and the International Scientific and Technology Cooperation Program of China ( 2015DFA31490 ). This project partly utilized University of Pittsburgh Cancer Institute shared resources supported by award P30CA047904 . G.K. is supported by the Ligue contre le Cancer Comit{\'e} de Charente-Maritime ({\'e}quipe labelis{\'e}e) ; Agence National de la Recherche (ANR) – Projets blancs ; ANR under the frame of E-Rare-2 , the ERA-Net for Research on Rare Diseases ; Association pour la recherche sur le cancer (ARC) ; Canc{\'e}rop{\^o}le {\^I}le-de-France ; Chancelerie des universit{\'e}s de Paris (Legs Poix) , Fondation pour la Recherche M{\'e}dicale (FRM) ; the European Commission ; the European Research Council (ERC); Fondation Carrefour ; Institut National du Cancer (INCa) ; Inserm (HTE) ; Institut Universitaire de France ; LeDucq Foundation ; the LabEx Immuno-Oncology ; the RHU Torino Lumi{\`e}re , the Searave Foundation ; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE) ; the SIRIC Cancer Research and Personalized Medicine (CARPEM) ; and the Paris Alliance of Cancer Research Institutes (PACRI) . Funding Information: We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US NIH (R01GM115366, R01CA160417, R01AT005076, R01GM063075, R01GM044100, and R01GM050441), the Natural Science Foundation of Guangdong Province (2016A030308011), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD), the National Natural Science Foundation of China (31671435, 81400132, and 81772508), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017), Lin He's Academician Workstation of New Medicine and Clinical Translation (2017), and the International Scientific and Technology Cooperation Program of China (2015DFA31490). This project partly utilized University of Pittsburgh Cancer Institute shared resources supported by award P30CA047904. G.K. is supported by the Ligue contre le Cancer Comit? de Charente-Maritime (?quipe labelis?e); Agence National de la Recherche (ANR) ? Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Canc?rop?le ?le-de-France; Chancelerie des universit?s de Paris (Legs Poix), Fondation pour la Recherche M?dicale (FRM); the European Commission; the European Research Council (ERC); Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumi?re, the Searave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jul,
day = "11",
doi = "10.1016/j.chom.2018.05.009",
language = "English",
volume = "24",
pages = "97--108.e4",
journal = "Cell Host and Microbe",
issn = "1931-3128",
number = "1",
}