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

被引：100

作者：

Wang, Dingyu ^{[1
,2
]}

Zheng, Jiashuo ^{[3
]}

Hu, Qiongyuan ^{[3
]}

Zhao, Cheng ^{[3
]}

Chen, Qianyue ^{[1
,2
]}

Shi, Peiliang ^{[1
,2
]}

Chen, Qin ^{[1
,2
]}

Zou, Yujie ^{[1
,2
]}

Zou, Dayuan ^{[1
,2
]}

Liu, Qiyao ^{[1
,2
]}

Pei, Jingwen ^{[1
,2
]}

Wu, Xiuwen ^{[3
]}

Gao, Xiang ^{[1
,2
]}

Ren, Jianan ^{[3
]}

Lin, Zhaoyu ^{[1
,2
]}

机构：

[1] Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Nanjing 210000, Peoples R China

[2] Nanjing Univ, MOE Key Lab Model Anim Dis Study, Model Anim Res Ctr, Nanjing 210000, Peoples R China

[3] Med Sch Nanjing Univ, Jinling Hosp, Res Inst Gen Surg, Nanjing 210000, Peoples R China

来源：

CELL DEATH AND DIFFERENTIATION | 2020年 / 27卷 / 02期

基金：

中国国家自然科学基金;

关键词：

NONCANONICAL INFLAMMASOME ACTIVATION; NLRP3; INFLAMMASOME; CASPASE-11; HYPOMAGNESEMIA; PORE; SUPPLEMENTATION; INJURY; GSDMD;

D O I：

10.1038/s41418-019-0366-x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：466 / 481

页数：16

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