Magnesium protects against sepsis by blocking gasdermin D N-terminal-induced pyroptosis

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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Acknowledgements

We thank XN Zhang, J. Liang, YY Dai, and Nanjing Biomedical Research Institute of Nanjing University for providing technical support. This work was supported by grants from the Ministry of Science and Technology of China (2015BAI08B02), the National Natural Science Foundation of China (31772550 and 31301217), the Key Project of Jiangsu Social Development (BE2016752), Natural Science Foundation in Jiangsu Province (BK20181260) and the Innovation Project of Military Medicine (16CXZ007).

Author information

DW, JZ, and ZL conceived this study, designed the experiments and wrote the paper. DW performed most of the experiments, assisted by JZ, Qianyue C, PS, Qin C, YZ, DZ, QL, and JP. JZ, QH, and CZ collected and analyzed the clinical data, supervised by XW and JR ZL and XG supervised all research.

Correspondence to Xiang Gao or Jianan Ren or Zhaoyu Lin.

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