Abstract Body: Introduction: Inflammation following myocardial ischemia/reperfusion injury (MI/R) plays a significant role in damaging cardiomyocytes and influencing infarct size, with neutrophils being the most rapid and numerous cells recruited to the myocardium post reperfusion. Single-cell RNA sequencing data identified neutrophils with upregulated type I interferon (IFN) signaling in the hearts of mice 24 hours post-MI/R.
Aim: This study aims to address how the type I IFN neutrophil phenotype identified affects inflammation in MI/R. We hypothesize that neutrophils with upregulated type I IFN signaling are cardioprotective in MI/R.
Methods: Male neutrophil-specific STING knockout (KO) mice underwent 60 minutes of ischemia followed by reperfusion for 24 hours. Immune cells were isolated from the left ventricle for flow cytometry. Subsequently, mice underwent 60 minutes of ischemia followed by reperfusion, and cardiac function was assessed two weeks-post reperfusion.
Results: Flow cytometry revealed a significant decrease in the number of neutrophils in the myocardium of neutrophil-specific STING KO mice compared to wildtype mice after 24 hours of reperfusion (5.7x10⁴ ± 1.0x10⁴; 8.7x10⁴ ± 1.9x10⁴, Two-way ANOVA, N=5-6, p=0.0006). Neutrophil-specific STING KO mice showed significant reduction in ejection fraction (29.2% ± 6.4) compared to wildtype mice (38.3% ± 6.7; Two-way ANOVA, N=4-5, p=0.036), and significantly increased left ventricular end systolic volume (4.39mm ± 0.48) compared to wildtype mice (3.59 ± 0.62; Two-way ANOVA, N=4-5, p=0.017), indicating impaired cardiac function in knockout mice.
Conclusion: These data suggest that neutrophil STING plays a cardioprotective role in MI/R. These studies provide the foundation to further investigate the cardioprotective mechanisms behind neutrophil-specific STING. Identifying a novel cardioprotective mechanism could be a clinically feasible point of intervention to improve recovery after MI/R.