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

J Clin Invest. 2022 Jan 4;132(1):e151268. doi: 10.1172/JCI151268.


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.

Keywords: Cardiology; Neutrophils.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Gene Knockout Techniques
  • Heart Failure* / etiology
  • Heart Failure* / genetics
  • Heart Failure* / metabolism
  • Heart Failure* / prevention & control
  • Male
  • Mice
  • Mice, Knockout
  • Myocardial Infarction* / complications
  • Myocardial Infarction* / genetics
  • Myocardial Infarction* / metabolism
  • Myocardium* / metabolism
  • Neutrophils* / metabolism
  • Phosphate-Binding Proteins* / genetics
  • Phosphate-Binding Proteins* / metabolism
  • Pore Forming Cytotoxic Proteins* / genetics
  • Pore Forming Cytotoxic Proteins* / metabolism
  • Ventricular Remodeling / genetics


  • Gsdmd protein, mouse
  • Phosphate-Binding Proteins
  • Pore Forming Cytotoxic Proteins