TLR7 Inhibition Limits Ischemic Cardiac Injury by Disrupting ITGAM-Dependent Immune-Endothelial Interactions.

Percutaneous coronary intervention, such as stenting, restores coronary perfusion after myocardial ischemia but also induces ischemia-reperfusion (I/R) injury, in part driven by innate immune activation. Here, we identified Toll-like receptor 7 (TLR7), an endosomal sensor of single-stranded RNA, as a key mediator of postischemic inflammation. Genetic deletion or pharmacologic inhibition of TLR7 with enpatoran reduced inflammation and myocardial infarction (MI) size and improved cardiac function 24 hours after I/R in mice. Single-nucleus RNA sequencing demonstrated coordinated induction of TLR7-responsive inflammatory endothelial and myeloid cell programs, including increased endothelial ITGAM expression and leukocyte adhesion. TLR7/8 activation promoted ITGAM-dependent endothelial-leukocyte interactions under shear stress, whereas ITGAM blockade reduced immune cell infiltration and limited MI injury. These findings identify the TLR7-ITGAM signaling axis as a central driver of endothelial-leukocyte crosstalk in myocardial I/R injury and support TLR7 inhibition as a promising therapeutic strategy to mitigate ischemic MI after percutaneous coronary intervention.