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

Rui Kang; Ling Zeng; Shan Zhu; Yangchun Xie; Jiao Liu; Qirong Wen; Lizhi Cao; Min Xie; Qitao Ran; Guido Kroemer; Haichao Wang; Timothy R Billiar; Jianxin Jiang; Daolin Tang

doi:10.1016/j.chom.2018.05.009

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

Cell Host Microbe. 2018 Jul 11;24(1):97-108.e4. doi: 10.1016/j.chom.2018.05.009. Epub 2018 Jun 21.

Authors

Rui Kang¹, Ling Zeng², Shan Zhu³, Yangchun Xie⁴, Jiao Liu³, Qirong Wen³, Lizhi Cao⁵, Min Xie⁵, Qitao Ran⁶, Guido Kroemer⁷, Haichao Wang⁸, Timothy R Billiar⁹, Jianxin Jiang¹⁰, Daolin Tang¹¹

Affiliations

¹ The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation Laboratory of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
² State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research Institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
³ The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation Laboratory of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
⁴ Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410008, China.
⁵ Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
⁶ Department of Cell Systems and Anatomy, University of Texas Health Science Center, Research Service, South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
⁷ Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Equipe 11 Labellisée Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; Institut National de La Santé et de La Recherche Médicale, U1138 Paris, France; Université Pierre et Marie Curie, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, 17176 Stockholm, Sweden.
⁸ Laboratory of Emergency Medicine, North Shore University Hospital, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
⁹ Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
¹⁰ State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research Institute for Traffic Medicine of People's Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China. Electronic address: jiangjx@cta.cq.cn.
¹¹ The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation Laboratory of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: tangd2@upmc.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Caspases / genetics
Caspases / metabolism
Caspases, Initiator
Coinfection / metabolism*
Disease Models, Animal
Escherichia coli / drug effects
Escherichia coli / pathogenicity
Glutathione Peroxidase / genetics
Glutathione Peroxidase / metabolism*
HL-60 Cells
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins
Leukocytes, Mononuclear / microbiology
Lipid Peroxidation / drug effects
Lipid Peroxidation / genetics*
Macrophages / microbiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphate-Binding Proteins
Phospholipid Hydroperoxide Glutathione Peroxidase
Pyroptosis / drug effects
Pyroptosis / genetics*
Sepsis / metabolism*
Vitamin E / pharmacology

Substances

Apoptosis Regulatory Proteins
Gsdmd protein, mouse
Intracellular Signaling Peptides and Proteins
Phosphate-Binding Proteins
Vitamin E
Phospholipid Hydroperoxide Glutathione Peroxidase
Glutathione Peroxidase
glutathione peroxidase 4, mouse
Casp4 protein, mouse
Caspases
Caspases, Initiator

Abstract

Publication types

MeSH terms

Substances

Grants and funding