Cardiomyocyte-derived Galectin-9 induces macrophage M2 polarization via the TIM3 pathway to attenuate myocardial remodeling post-myocardial infarction.

Abstract

M2 macrophages play a key role in tissue repair during the late stages of myocardial infarction (MI). This study highlights the influence of cardiomyocyte-derived Galectin-9 on macrophage function post-MI. Using a murine model with left anterior descending (LAD) artery ligation, we examined the effects of Galectin-9 deficiency, exogenous Galectin-9 supplementation, and macrophage depletion on myocardial macrophage polarization and tissue remodeling. Our results showed increased Galectin-9 expression in infarcted myocardial tissue. Galectin-9 deficiency impaired cardiac recovery and reduced M2 macrophage presence in the infarcted area. Supplementation with exogenous Galectin-9 improved tissue remodeling in Galectin-9-deficient mice and increased M2 macrophage levels. However, macrophage depletion negated the benefits of Galectin-9 supplementation, exacerbating cardiac dysfunction. In vitro, Galectin-9 enhanced the M2 phenotype in macrophage-like RAW264.7 cells after hypoxic preconditioning of cardiomyocytes. This effect was diminished when cardiomyocytes lacked Galectin-9. TIM3 knockdown in RAW264.7 cells reversed the M2 polarization induced by recombinant Galectin-9 and inhibited the PI3K/Akt signaling pathway. These findings suggest that injured cardiomyocytes release Galectin-9 after MI, which binds to TIM3 on macrophages, activating the PI3K/Akt pathway to promote M2 polarization. This cardiomyocyte-macrophage interaction mitigates myocardial remodeling and helps preserve cardiac function after MI.