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bioRxiv · 10.1101/2024.09.06.611551

The Cardioprotective Role of Neutrophil-Specific STING in Myocardial Ischemia/Reperfusion Injury

Brockman, M. L.·Scruggs, T. A.·Wang, L.·Kabboul, G.·Calvert, J. W.·Levit, R. D.
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Abstract

BackgroundNeutrophils are the most rapid and abundant immune cells to infiltrate the myocardium following myocardial ischemia/reperfusion injury (MI/R). Neutrophil heterogeneity has not been well characterized in MI/R, and studies have shown conflicting results regarding the impact of neutrophil depletion on cardiac injury. We thus aim to study the impact of neutrophils with enriched type I interferon signature and the role of STING (stimulator of interferon genes) signaling in neutrophils on cardiac reperfusion injury. MethodsWe utilized single-cell RNA sequencing to study neutrophil heterogeneity in response to MI/R. We generated a neutrophil-specific STING knockout mouse to assess the role of neutrophil STING in a model of MI/R. We examined cardiac function following injury via echocardiography and assessed the immune cell trajectory following injury utilizing flow cytometry. ResultsWe identified a population of neutrophils with enriched type I interferon signaling and response to type I interferon following MI/R. We found that genetic deletion of neutrophil-specific STING led to worsened cardiac function following MI/R. Further investigation of the immune response by flow cytometry revealed decreased neutrophil infiltration into the myocardium and a shift in macrophage polarization. ConclusionsOur findings suggest that neutrophil-specific STING is cardioprotective in MI/R, partly due to its effects on downstream immune cells. These results demonstrate that early alterations or therapeutic interventions can influence key events in the resolution of inflammation following MI/R.

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Brockman, M. L., Scruggs, T. A., Wang, L., Kabboul, G., Calvert, J. W., Levit, R. D.. 2024-09-11. The Cardioprotective Role of Neutrophil-Specific STING in Myocardial Ischemia/Reperfusion Injury. https://doi.org/10.1101/2024.09.06.611551

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