Gasdermin D inhibition confers antineutrophil-mediated cardioprotection in acute myocardial infarction
Kai Jiang, Zizhuo Tu, Kun Chen, Yue Xu, Feng Chen, Sheng Xu, Tingting Shi, Jie Qian, Lan Shen, John Hwa, Dandan Wang, Yaozu Xiang
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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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 4

GSDMD is essential for recruitment of neutrophils/monocytes to the infarcted heart.

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GSDMD is essential for recruitment of neutrophils/monocytes to the infar...
(A and B) Flow cytometric analysis and quantification of Cd11b+Ly6G+ neutrophils and Cd11b+Ly6C+ monocytes in the heart (left), blood (middle), or BM (right) from WT or Gsdmd−/− mice 72 hours after AMI (n = 7–15). (C) Immunofluorescence imaging and magnification for MPO (red), TUNEL (green), and DAPI (blue) on heart sections from WT or Gsdmd−/− mice 24 hours after AMI. Scale bar: 20 μm. (D and E) Quantification of ratios of MPO+ or TUNEL+ cells of heart sections from WT or Gsdmd−/− mice. Each value was averaged from the values of 7 fields of view from the same mouse (n = 3 per group). (F) Immunofluorescence imaging of heart sections from WT or Gsdmd−/− mice 3 days after AMI showing α-actinin (red), CD68 (green), and DAPI (blue). Representative fields of remote zone, border zone, and infarct zone are presented. Scale bar: 20 μm. (G and H) Quantification of CD68+ area proportion in the field of view in remote zone (G) and border and infarct zones (H) of heart sections from WT or Gsdmd−/− mice. Each value was averaged from the values of 5 fields of view from the same mouse (n = 3 per group). Data are presented as mean ± SD. *P < 0.05; ****P < 0.0001 by multiple 2-tailed Student’s t test (B) or unpaired, 2-tailed Student’s t test (D, E, G, and H). NS, not significant.