Abstract
Introduction: Inflammation following myocardial ischemia/reperfusion (MI/R) plays a significant role in damaging cardiomyocytes and influencing infarct size, with neutrophils being the most rapid and numerous cells in the post-MI/R heart at 24 hours post reperfusion. Preliminary single-cell RNA sequencing data shows type I interferon (IFN) responding neutrophils are present in the hearts of mice 24 hours post-MI/R. The following study aims to address how the type I IFN responding neutrophil phenotype identified in single-cell RNA sequencing data affects cardiac inflammation in MI/R. We hypothesize that STING and type I IFN activation in neutrophils in the early stages of inflammation can exacerbate inflammation, causing further damage to the heart in MI/R. Methods: Male C57BL/6J mice (10-11 weeks old) underwent 60 minutes of ischemia followed by reperfusion, and were dosed with either vehicle, a STING inhibitor (H151), or an IFNAR1 antibody (ab) at reperfusion and at 24 hours following reperfusion. Cardiac function was assessed two weeks post-reperfusion via echocardiography and tissue samples were collected for histological analysis. Results: Mice treated with IFNAR1 ab showed significant improvement in ejection fraction (44.9% ± 6.8) compared to mice treated with vehicle (31.9% ± 6.2; One-way ANOVA, N=5-6, p<0.05). Additionally, mice treated with IFNAR1 ab showed significant improvements in left ventricular end systolic volume (LVESD) (3.16mm ± 0.52) compared to vehicle treated mice (3.89mm ± 0.40; One-way ANOVA, N=5-6, p<0.05). Mice treated with H151 showed significant improvement in ejection fraction (43.8% ± 7.1) compared to mice treated with vehicle (31.9% ± 6.2; One-way ANOVA, N=5-6, p<0.05). Treatment with H151 or IFNAR1 ab reduced scar size (7.22% ± 3.6; 7.88% ± 3.1%) compared to mice treated with vehicle (9.74% ± 3.7; N=5-6). Conclusion: These data show that targeting the early IFN response in MI/R can improve cardiac function, and provide a basis for studies identifying the effects of the neutrophil specific STING and type I IFN activation following MI/R. If correct, this pathway could be a powerful and clinically feasible point of intervention to improve cardiac recovery after MI/R.
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