Recombinant CCL2 improved cardiac function, reduced infarct size, and promoted M2 macrophage polarization via the CCR2-CH25H-mTOR-AMPK axis in mice post-myocardial infarction.
Does recombinant CCL2 improve cardiac function and reduce remodeling post-myocardial infarction in mice?
CCL2 confers cardioprotection and ameliorates post-MI remodeling by driving reparative macrophage M2 polarization through a novel CCR2-CH25H-mTOR-AMPK pathway.
Myocardial infarction (MI) triggers intense inflammation that drives adverse ventricular remodeling and heart failure. The chemokine CCL2 is upregulated post-MI, but its specific role in cardiac repair remains controversial. This study investigated the therapeutic potential and mechanism of CCL2 in post-MI remodeling. MI was induced in mice, which were then treated with recombinant CCL2 (rCCL2). rCCL2 significantly improved cardiac function, reduced infarct size and fibrosis, and attenuated cardiomyocyte apoptosis. Flow cytometry revealed that CCL2 skewed the cardiac immune response toward an anti-inflammatory state, promoting M2 macrophage polarization and increasing regulatory T cells. In bone marrow-derived macrophages (BMDMs), RNA-seq identified cholesterol 25-hydroxylase (CH25H) as a key downstream effector. Mechanistically, CCL2 binding to CCR2 upregulated CH25H, which inhibited mTORC1 and activated AMPK, leading to STAT6 phosphorylation. This cascade enhanced oxidative phosphorylation and mitochondrial mass, driving M2 polarization. Critically, pharmacological inhibition of either CCR2 or AMPK abolished these benefits. We conclude that CCL2 confers cardioprotection by promoting reparative macrophage polarization via a novel CCR2-CH25H-mTOR-AMPK signaling axis, identifying this pathway as a promising therapeutic target for improving post-MI outcomes.
Yang et al. (Tue,) conducted a other in Myocardial infarction. recombinant CCL2 (rCCL2) was evaluated on cardiac function, infarct size, fibrosis, and cardiomyocyte apoptosis. Recombinant CCL2 improved cardiac function, reduced infarct size, and promoted M2 macrophage polarization via the CCR2-CH25H-mTOR-AMPK axis in mice post-myocardial infarction.