Sex-specific and immune-cell-specific contributions of beta2 integrins in myocardial ischemia-reperfusion injury

Leukocyte recruitment and their mediated inflammatory responses are critical for cardiovascular diseases, including myocardial ischemia-reperfusion (I/R) injury, which accounts for 9% mortality and 10% morbidity rates in ischemic heart disease patients. Blocking leukocyte recruitment in mouse knockouts (KO) of beta2 integrin (CD18) or blocking beta2 integrin with anitibodies in multiple animals significantly reduced infarct size after myocardial I/R injury. However, the cell-specific contribution of leukocyte beta2 integrin to I/R injury is unknown. In this study, we used the newly established CD18flox/flox (hITGB2 KI) mouse strain to address this knowledge gap. We crossed them to CSF1R-cre (CD115) and MRP8-cre (S100A8) and tested the KO of beta2 integrins in different leukocyte populations. Interestingly, CSF1R-cre CD18flox/flox unexpectedly deleted beta2 integrins in all peripheral blood leukocyte populations, including blood neutrophils, monocytes, CD4 T cells, CD8 T cells, B cells, and NK cells. It also elevated the cell number of these leukocyte populations in peripheral blood. In MRP8-cre CD18flox/flox mice, beta2 integrins were only knocked out in neutrophils but not other peripheral blood leukocytes. And only neutrophil number was elevated in peripheral blood. After 35 minutes of myocardial ischemia and 24 hours of reperfusion, we found both CSF1R-cre CD18flox/flox and MRP8-cre CD18flox/flox mice have significantly reduced infarct size compared to cre- controls. However, if we distinguish the sex in analysis, we only found a significant alleviation in female but not male CSF1R-cre CD18flox/flox mice. In contrast, we observed a significant alleviation only in male but not female MRP8-cre CD18flox/flox mice. These results suggested sex-specific and immune-cell-specific contributions of beta2 integrins in myocardial ischemia-reperfusion injury and provided new insights into beta2 integrin targeting therapies. This research was supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute, USA (R01HL145454, R41HL156322, and R44HL152710) and a startup fund from UConn Health. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.