TLR7 inhibition limits cardiac ischemic injury by disrupting ITGAM-dependent immune–endothelial interaction

Percutaneous coronary intervention (PCI) limits ischemic myocardial infarction but also triggers ischemia-reperfusion (I/R) injury in part driven by innate immune activation. Here, we identify Toll-like receptor 7 (TLR7), an endosomal sensor of single-stranded RNA, as a mediator of post-ischemic inflammation and myocardial damage. Pharmacological inhibition of TLR7 with enpatoran reduced myocardial inflammation and infarct size and improved cardiac function in a mouse model of I/R injury when administered before, during, or shortly after ischemia. Single-nucleus RNA sequencing revealed coordinated post-I/R expansion of myeloid cells and distinct inflammatory endothelial subsets enriched for leukocyte-interaction programs, with marked upregulation of <i>Itgam</i> in cardiac leukocytes and endothelial cells and in circulating monocytes. Circulating <i>ITGAM</i> ⁺ monocytes were similarly increased in patients with ST-segment elevation myocardial infarction 24 hours after coronary stenting. Mechanistically, TLR7 activation induced <i>Itgam</i> expression in endothelial cells and leukocytes and promoted their adhesion via ITGAM-ICAM1 interaction under physiological shear stress, whereas ITGAM neutralization disrupted this interaction, reduced immune cell infiltration, and limited ischemic injury. These findings define a TLR7-ITGAM signaling axis as a key driver of endothelial-leukocyte crosstalk in myocardial I/R injury and support TLR7 inhibition as a promising therapeutic strategy to mitigate acute myocardial infarction.