NLRC5 and NF-κB Signaling: Implications for Atherosclerotic Plaque Formation in Acute Coronary Syndromes

Abstract

This study assessed the role of nucleotide-binding domain and leucine-rich repeat containing receptor, caspase recruitment domain containing 5 (NLRC5) in macrophages in atherosclerotic plaque formation in acute coronary syndromes (ACS) by modulating the nuclear factor-kappaB (NF-κB) cascade. Peripheral blood was obtained from ACS patients and matched controls, and NLRC5 expression and DNA methylation were analyzed. In vitro, peripheral blood mononuclear cells from donors were induced into macrophage-derived foam cells and transfected with small interfering RNA negative control (si-NC) or si-NLRC5 plasmids to assess foam cell formation and cytokine release. In vivo, ApoE^−/− mice fed a high-fat diet and subjected to NLRC5 silencing were used as an ACS model. Peritoneal macrophage phagocytosis, aortic lipid accumulation, plaque size, and collagen fiber content were evaluated, while lipid metabolism- and inflammation-related genes were measured in foam cells and aortas. NLRC5 was highly expressed and hypomethylated in ACS patients. NLRC5 knockdown suppressed foam cell formation and inflammation in vitro. In ACS mice, silencing NLRC5 reduced lipid levels and cytokines, inhibited lipid deposition, decreased plaque size, and enhanced collagen fiber content through NF-κB pathway inhibition. These findings suggest that NLRC5 silencing may protect against atherosclerosis in ACS by regulating macrophage function and inflammatory signaling.