LILRB4 exacerbates myocardial ischemia-reperfusion injury by promoting inflammation and pyroptosis.

Inflammation and pyroptosis are pivotal in myocardial ischemia-reperfusion injury. Although leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) modulates inflammation in conditions such as myocardial hypertrophy, its involvement in myocardial ischemia-reperfusion injury (MIRI) remains ambiguous. Recombinant adenoviral vectors were designed to induce the overexpression or knockdown of LILRB4 in H9C2 cardiomyocytes or rat myocardial tissue. H9C2 cells were subjected to hypoxia for 2 h and reoxygenation for 4 h (H/R), while myocardial tissue experienced 30 min of ischemia followed by 2 h of reperfusion (I/R). Biochemical assay, histopathology, ELISA, and other tests were performed on myocardial cells and tissues. Meanwhile, LILRB4 knockout mice were used for further validation. LILRB4 promotes the release of inflammatory factors induced by I/R and H/R, thereby increasing the size of myocardial infarction and leading to functional impairment. Downregulation of LILRB4 suppressed SHP-2 phosphorylation and activation, consequently reducing the expression of the thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), Caspase-1, and Gasdermin D (GSDMD). The SHP2 inhibitor PHPS1 mitigated the inflammatory and pyroptotic effects of LILRB4 in cardiomyocytes induced by H/R. Compared to wild-type mice, LILRB4-/- mice exhibited markedly diminished myocardial tissue swelling, decreased release of inflammatory cytokines, and a notable reduction in the expression of p-SHP2, TXNIP, NLRP3, Caspase-1, and GSDMD proteins after I/R induction.LILRB4 promotes inflammation and pyroptosis, which in turn worsens MIRI, likely through activating the TXNIP/NLRP3 signaling pathway, providing mechanistic insights into the MIRI.