Gasdermin D inhibition confers antineutrophil-mediated cardioprotection in acute myocardial infarction
Kai Jiang, … , Dandan Wang, Yaozu Xiang
Kai Jiang, … , Dandan Wang, Yaozu Xiang
Published November 9, 2021
Citation Information: J Clin Invest. 2022;132(1):e151268. https://doi.org/10.1172/JCI151268.
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Research Article Cardiology

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

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.

Authors

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

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Figure 6

GSDMD deficiency suppresses cell death and IL-1β secretion.

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GSDMD deficiency suppresses cell death and IL-1β secretion. (A) Schemati...
(A) Schematic diagram showing the strategy of preparing samples for IL-1β and lactate dehydrogenase (LDH) detection in Cd11b+ myeloid-derived cells and neutrophils from the heart. Neu+, neutrophils; Neu–, neutrophil free. (B) Secretion levels of LDH from leukocytes from the heart of WT or Gsdmd−/− mice 24 hours and 72 hours after AMI. (C) Production of IL-1β from Cd11b+ cells from the heart of WT or Gsdmd−/− mice 24 hours and 72 hours after AMI assessed by ELISA. The corresponding n values are indicated in the plot. (D) Secretion levels of LDH from neutrophils isolated from the heart of WT or Gsdmd−/− mice 24 hours and 72 hours after AMI. (E) Production of IL-1β from neutrophils isolated from the heart of WT or Gsdmd−/− mice 24 hours and 72 hours after AMI assessed by ELISA. The corresponding n values are indicated in the plot. (F and G) Representative immunoblotting images (F) and quantification (G) of protein levels in heart left ventricular tissues from WT or Gsdmd−/− mice 24 hours after AMI or sham surgery (n = 3 per group). (H and I) Representative immunoblotting images (H) and quantification (I) of protein levels of heart Cd11b+ cells from WT or Gsdmd−/− mice 72 hours after AMI or sham surgery (n = 3–5). Data are presented as mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, as analyzed by unpaired, 2-tailed Student’s t test (B–E and I) or 1-way ANOVA with Tukey’s correction for multiple comparisons (G). NS, not significant.