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

Kai Jiang,Zizhuo Tu,Jie Qian,Kun Chen,Lan Shen,Feng Chen,Yue Xu,John Hwa,Tingting Shi,Dandan Wang,Sheng Xu,Yaozu Xiang

doi:10.1172/jci151268

Abstract

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-1β 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.

Highlights

Acute myocardial infarction (AMI) is a leading cause of death worldwide
Expressed genes (DEGs) that had consistent expression patterns across sham, day 1 AMI, and day 7 AMI were further clustered together, and genes encoding the components of the inflammasome showed a distinct increase, indicating the inflammasome may be activated after AMI (Figure 1, B and C, and Supplemental Figure 1)
Both expression and activation of gasdermin D (GSDMD) in heart were remarkably enhanced in response to myocardial ischemia/infarction in left anterior descending (LAD) ligation–operated wild type (WT) mice, as early as 24 hours after AMI (Figure 1, E and F)

Summary

Introduction

Acute myocardial infarction (AMI) is a leading cause of death worldwide. Reperfusion is successful in reducing infarct size and improving overall prognosis, AMI remains a major cause of heart failure and increased morbidity and mortality [1]. In the past 2 decades, an increase in programmed cardiomyocyte cell death has been recognized in AMI and ischemia–reperfusion (I/R) injury [1, 2]. Sudden massive loss of cardiomyocytes after AMI exceeds the limited regenerative capacity of the myocardium [3]. Cytokines released from necrotic cells can activate innate immune pathways, triggering an intense inflammatory response [4]. Dysregulation of the inflammatory response may cause adverse remodeling (fibrosis and scar formation) in patients with AMI, contributing to postinfarction heart failure [5]. Therapeutic attempts to suppress inflammation during AMI can lead to impaired cardiac repair and increased risk of cardiac rupture [6]. More recent strategies aimed at selectively blocking key inflammatory factors rather than globally suppressing the response have shown some promising results [7]

Methods

Results

Conclusion