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.
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.
Cell Host Microbe. 2018 Jul 11;24(1):97-108.e4. doi: 10.1016/j.chom.2018.05.009. Epub 2018 Jun 21.
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.
脓毒症是一种由病原体感染引起的危及生命的疾病，与细胞焦亡有关。细胞焦亡是在促炎半胱天冬酶被激活及其随后对gasdermin D (GSDMD)的切割作用下发生的，导致 GSDMD N 端片段形成膜孔，从而诱导细胞裂解。在这里，我们发现抗氧化防御酶谷胱甘肽过氧化物酶 4 (GPX4)及其降低脂质过氧化的能力可负调控巨噬细胞焦亡和小鼠脓毒症的致死率。条件性 Gpx4 基因敲除可增加依赖于脂质过氧化的 caspase-11 的激活和 GSDMD 的切割。由此产生的 N 端 GSDMD 片段随后以依赖于磷脂酶 Cγ1 (PLCγ1)的方式触发巨噬细胞焦亡性细胞死亡。给予抗氧化维生素 E 以减少脂质过氧化、化学抑制 PLCγ1、或基因敲除 Caspase-11 或 Gsdmd 失活可防止 Gpx4 小鼠发生多微生物脓毒症。总的来说，这项研究表明，脂质过氧化驱动 GSDMD 介导的细胞焦亡，因此构成了致命感染的潜在治疗靶点。
