Trem2 regulates macrophage phenotype via the JAK2/STAT3 signaling pathway to ameliorate ventricular remodeling after acute myocardial infarction.

BACKGROUND: Pathological ventricular remodeling after acute myocardial infarction (AMI) is a critical pathological basis of heart failure, with macrophages as the core driver of inflammatory imbalance. Trem2-expressing macrophages regulate inflammation resolution and tissue repair, and the JAK2/STAT3 pathway is involved in macrophage phenotype modulation. However, whether Trem2 regulates macrophage polarization and improves ventricular remodeling via this pathway post-AMI remains unclear. This study aimed to explore the regulatory role of the Trem2-JAK2/STAT3 axis in macrophage polarization and ventricular remodeling after AMI. METHODS: Dynamic Trem2 expression was detected in a mouse AMI model. Myeloid-specific Trem2 knockout mice (Mac-Trem2KO) were generated, and cardiac function, infarct size, cardiomyocyte apoptosis, collagen deposition and survival rate were compared between knockout and control groups. The GSE218002 dataset and myocardial tissues were used to verify the effect of Trem2 deficiency on macrophage phenotypes. sTREM2 supplementation and AG490 inhibition were performed to verify the JAK2/STAT3 pathway-mediated regulatory mechanism. RESULTS: Trem2 expression was upregulated after AMI and peaked at the repair phase. Compared with controls, Mac-Trem2KO mice showed more severe ventricular remodeling and cardiac dysfunction. Trem2 deficiency suppressed JAK2/STAT3 pathway activation and skewed macrophages toward a pro-inflammatory phenotype. Exogenous sTREM2 restored pathway activity and ameliorated cardiac function, while AG490 recapitulated the cardiac dysfunction induced by Trem2 deficiency. CONCLUSION: Trem2 mediates macrophage phenotypic switching by activating the JAK2/STAT3 pathway in macrophages, thus inhibiting pathological ventricular remodeling. The Trem2-JAK2/STAT3 signaling axis represents a promising therapeutic target for post-AMI myocardial remodeling.