Epigenetic upregulation of CLEC5A contributes to monocyte/macrophage dysfunction in coronary artery disease

Inflammatory activation and dysfunction of immune cells are essential events in coronary artery disease (CAD) pathogenesis. C-type lectin domain family 5 member A (CLEC5A) has recently been regarded as a potent modulator of inflammation, while its contribution to CAD remains undefined. This study aims to clarify the involvement of CLEC5A in atherosclerosis and explore its epigenetic regulatory mechanisms. Integrated methylome and transcriptome analyses identified CLEC5A as a DNA methylation-driven gene in CAD. Functional studies revealed that DNMT1 overexpression suppresses CLEC5A expression in THP-1 cells, with subsequent identification of the cg06744540 CpG site as the critical regulatory locus. Clinical correlation analyses demonstrated that elevated CLEC5A expression is inversely associated with hypomethylation at cg06744540 in CAD patients. Furthermore, CLEC5A overexpression significantly enhanced monocyte inflammation, migration, and adhesion, promoted macrophage polarization and lipid accumulation, and inhibited apoptosis. Mechanistic investigations revealed that CLEC5A exacerbates inflammation in monocyte/macrophage by activating the NF-κB signaling pathway. Conversely, CLEC5A knockdown resulted in opposite effects. Notably, treatment of cells with folic acid, a methylation-enhancing factor, significantly increased DNMT1 expression and declined CLEC5A expression. Consistently, folic acid reversed high-fat-induced CLEC5A expression and inflammation and suppressed the formation of atherosclerotic plaques in vivo. In conclusion, the epigenetic upregulation of CLEC5A through DNMT1-mediated cg06744540 demethylation contributed to monocyte/macrophage dysfunction, thus accelerating CAD progression.