CCL2はCH25Hを介した代謝再プログラミングを駆動して心筋梗塞後のリモデリングを改善し、マクロファージM2分極を促進する

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.