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bioRxiv · 10.64898/2026.01.17.698774

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

Li, Y.·Yang, Y.·Park, C.·Ren, B.·Li, R.·Shetty, A. C.·Williams, B.·Li, Z.·Chao, W.
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Abstract

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 Itgam in cardiac leukocytes and endothelial cells and in circulating monocytes. Circulating ITGAM+ monocytes were similarly increased in patients with ST-segment elevation myocardial infarction 24 hours after coronary stenting. Mechanistically, TLR7 activation induced Itgam 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.

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Li, Y., Yang, Y., Park, C., Ren, B., Li, R., Shetty, A. C., Williams, B., Li, Z., Chao, W.. 2026-01-21. TLR7 inhibition limits cardiac ischemic injury by disrupting ITGAM-dependent immune-endothelial interaction. https://doi.org/10.64898/2026.01.17.698774

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