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

共 42 条

[31] Effect of magnesium supplementation and depletion on the onset and course of acute experimental pancreatitis [J].

Schick, Verena ;

Scheiber, Jonas A. ;

Mooren, Frank C. ;

Turi, Stefan ;

Ceyhan, Gueralp O. ;

Schnekenburger, Juergen ;

Sendler, Matthias ;

Schwaiger, Theresa ;

Omercevic, Armin ;

van den Brandt, Cindy ;

Fluhr, Gabriele ;

Domschke, Wolfram ;

Krueger, Burkhard ;

Mayerle, Julia ;

Lerch, Markus M. .

GUT, 2014, 63 (09) :1469-1480

[32] Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells [J].

Schmid-Burgk, Jonathan L. ;

Gaidt, Moritz M. ;

Schmidt, Tobias ;

Ebert, Thomas S. ;

Bartok, Eva ;

Hornung, Veit .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2015, 45 (10) :2911-2917

[33] Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death [J].

Shi, Jianjin ;

Zhao, Yue ;

Wang, Kun ;

Shi, Xuyan ;

Wang, Yue ;

Huang, Huanwei ;

Zhuang, Yinghua ;

Cai, Tao ;

Wang, Fengchao ;

Shao, Feng .

NATURE, 2015, 526 (7575) :660-665

[34] Inflammatory caspases are innate immune receptors for intracellular LPS [J].

Shi, Jianjin ;

Zhao, Yue ;

Wang, Yupeng ;

Gao, Wenqing ;

Ding, Jingjin ;

Li, Peng ;

Hu, Liyan ;

Shao, Feng .

NATURE, 2014, 514 (7521) :187-+

[35] Development of ionized hypomagnesemia is associated with higher mortality rates [J].

Soliman, HM ;

Mercan, D ;

Lobo, SSM ;

Mélot, C ;

Vincent, JL .

CRITICAL CARE MEDICINE, 2003, 31 (04) :1082-1087

[36] Altered cytokine production in mice lacking P2X7 receptors [J].

Solle, M ;

Labasi, J ;

Perregaux, DG ;

Stam, E ;

Petrushova, N ;

Koller, BH ;

Griffiths, RJ ;

Gabel, CA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (01) :125-132

[37] Admission hypomagnesemia linked to septic shock in patients with systemic inflammatory response syndrome [J].

Thongprayoon, Charat ;

Cheungpasitporn, Wisit ;

Erickson, Stephen B. .

RENAL FAILURE, 2015, 37 (09) :1518-1521

[38]

Velissaris Dimitrios, 2015, J Clin Med Res, V7, P911, DOI 10.14740/jocmr2351w

[39] Effects of divalent cations, protons and calmidazolium at the rat P2X(7) receptor [J].

Virginio, C ;

Church, D ;

North, RA ;

Surprenant, A .

NEUROPHARMACOLOGY, 1997, 36 (09) :1285-1294

[40] Hypomagnesemia and Inflammation: Clinical and Basic Aspects [J].

Weglicki, William B. .

ANNUAL REVIEW OF NUTRITION, VOL 32, 2012, 32 :55-+

← 1 2 3 4 5 →