Gasdermin D inhibition confers antineutrophil-mediated cardioprotection in acute myocardial infarction

被引：70

作者：

Jiang, Kai ^{[1
]}

Tu, Zizhuo ^{[1
]}

Chen, Kun ^{[1
]}

Xu, Yue ^{[1
]}

Chen, Feng ^{[1
]}

Xu, Sheng ^{[2
]}

Shi, Tingting ^{[2
]}

Qian, Jie ^{[1
]}

Shen, Lan ^{[3
]}

Hwa, John ^{[4
]}

Wang, Dandan ^{[1
]}

Xiang, Yaozu ^{[1
,2
]}

机构：

[1] Tongji Univ, Shanghai East Hosp, Sch Life Sci & Technol, Key Lab Arrhythrnias,Minist Educ China, Shanghai, Peoples R China

[2] Tongji Univ, Shanghai Peoples Hosp 10, Sch Med, Shanghai, Peoples R China

[3] Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Dept Cardiol, Clin Res Unit, Shanghai, Peoples R China

[4] Yale Univ, Sch Med, Dept Internal Med, Sect Cardiovasc Med,Yale Cardiovasc Res Ctr, New Haven, CT 06510 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2022年 / 132卷 / 01期

基金：

中国国家自然科学基金;

关键词：

INFLAMMATORY RESPONSE; PYROPTOSIS; REPAIR; INTERLEUKIN-1; GSDMD;

D O I：

10.1172/JCI151268

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Acute myocardial infarction (AMI) induces blood leukocytosis, which correlates inversely with patient survival. The molecular mechanisms leading to leukocytosis in the infarcted heart remain poorly understood. Using an AMI mouse model, we identified gasdermin D (GSDMD) in activated leukocytes early in AMI. We demonstrated that GSDMD is required for enhanced early mobilization of neutrophils to the infarcted heart, Loss of GSDMD resulted in attenuated IL-1 beta release from neutrophils and subsequent decreased neutrophils and monocytes in the infarcted heart. Knockout of GSDMD in mice significantly reduced infarct size, improved cardiac function, and increased post-AMI survival. Through a series of bone marrow transplantation studies and leukocyte depletion experiments, we further clarified that excessive bone marrow-derived and GSDMD-dependent early neutrophil production and mobilization (24 hours after AMI) contributed to the detrimental immunopathology after AMI. Pharmacological inhibition of GSDMD also conferred cardioprotection after AMI through a reduction in scar size and enhancement of heart function. Our study provides mechanistic insights into molecular regulation of neutrophil generation and mobilization after AMI, and supports GSDMD as a new target for improved ventricular remodeling and reduced heart failure after AMI.

引用

页数：17

共 34 条

[1] Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease [J].