NK Cells Promote Macrophage Foam Cell Formation via TIGIT/CD155-Mediated Cholesterol Metabolism

Macrophage foaming, characterized by uncontrolled uptake of oxidized LDL (ox-LDL) by macrophages, critically drives atherosclerosis (AS) progression. Although NK cells are found to be atherogenic, their direct impact on macrophage foaming remains unknown. Here we examined the role of NK cells in macrophage foaming and found that NK cells exacerbated macrophage cholesterol accumulation both in the presence/absence of ox-LDL. Under ox-LDL exposure, NK cells promoted cholesterol accumulation via increasing cholesterol influx related gene CD36, and significantly reducing the expressions of cholesterol efflux associated receptors ABCA1 and ABCG1 in the macrophages. When without ox-LDL, NK cells accelerated cholesterol synthesis via the SREBP-2-LDLR/HMGCR pathway, and inhibited cholesterol efflux via the LXR-α-ABCA1/ABCG1 pathway of macrophages. These factors eventually led to the accumulation of cholesterol in macrophages, resulting in the formation of macrophage foam cells. Further, for the first time, we revealed the TIGIT/CD155 signaling pathway as a critical regulatory mechanism for macrophage foam cell formation. Specifically, the downregulation of TIGIT in highly active NK cells altered its interaction with CD155, which influenced macrophage cholesterol metabolism via CD155 and ultimately promoted foam cell formation. Furthermore, direct blockade of CD155 on macrophages exacerbated cholesterol accumulation, thereby establishing CD155 as an important regulator in macrophage-derived foam cell formation. These findings not only confirm NK cells as important drivers of macrophage foam cell formation but also highlight CD155 as a potential therapeutic target for atherosclerosis.