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Magnesium protects against sepsis by blocking gasdermin D N-terminal-induced pyroptosis.
Wang, Dingyu; Zheng, Jiashuo; Hu, Qiongyuan; Zhao, Cheng; Chen, Qianyue; Shi, Peiliang; Chen, Qin; Zou, Yujie; Zou, Dayuan; Liu, Qiyao; Pei, Jingwen; Wu, Xiuwen; Gao, Xiang; Ren, Jianan; Lin, Zhaoyu.
Affiliation
  • Wang D; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China.
  • Zheng J; Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, 210000, Nanjing, China.
  • Hu Q; Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, 210000, Nanjing, China.
  • Zhao C; Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, 210000, Nanjing, China.
  • Chen Q; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China.
  • Shi P; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China.
  • Chen Q; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China.
  • Zou Y; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China.
  • Zou D; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China.
  • Liu Q; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China.
  • Pei J; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China.
  • Wu X; Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, 210000, Nanjing, China.
  • Gao X; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China. gaoxiang@nju.edu.cn.
  • Ren J; Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, 210000, Nanjing, China. jiananr@gmail.com.
  • Lin Z; State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China. linzy@nju.edu.cn.
Cell Death Differ ; 27(2): 466-481, 2020 02.
Article in En | MEDLINE | ID: mdl-31209359
ABSTRACT
Hypomagnesemia is a significant risk factor for critically ill patients to develop sepsis, a life-threatening disease with a mortality rate over 25%. Our clinic data analysis showed that hypomagnesemia is associated with a decreased monocyte count in septic patients. At the cellular level, we found that Mg2+ inhibits pyroptosis. Specifically, Mg2+ limits the oligomerization and membrane localization of gasdermin D N-terminal (GSDMD-NT) upon the activation of either the canonical or noncanonical pyroptotic pathway. Mechanistically, we demonstrated that Ca2+ influx is a prerequisite for the function of GSDMD-NT. Mg2+ blocks Ca2+ influx by inhibiting the ATP-gated Ca2+ channel P2X7, thereby impeding the function of GSDMD-NT and inhibiting lipopolysaccharide (LPS)-induced noncanonical pyroptosis. Furthermore, Mg2+ administration protects mice from LPS-induced lethal septic shock. Together, our data reveal the underlying mechanism of how Mg2+ inhibits pyroptosis and suggest potential clinic applications of magnesium supplementation for sepsis prevention and treatment.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Sepsis / Phosphate-Binding Proteins / Intracellular Signaling Peptides and Proteins / Pyroptosis / Magnesium Type of study: Risk_factors_studies Limits: Animals / Humans / Male Language: En Journal: Cell Death Differ Year: 2020 Type: Article Affiliation country: China
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Sepsis / Phosphate-Binding Proteins / Intracellular Signaling Peptides and Proteins / Pyroptosis / Magnesium Type of study: Risk_factors_studies Limits: Animals / Humans / Male Language: En Journal: Cell Death Differ Year: 2020 Type: Article Affiliation country: China