Siglec‐E Retards Atherosclerosis by Inhibiting CD36‐Mediated Foam Cell Formation

The accumulation of lipid‐laden macrophages, foam cells, within sub‐endothelial intima is a key feature of early atherosclerosis. Siglec‐E is a member of sialic acid binding lectin predominantly expressed on myeloid cells to transduce inhibitory signal upon interacting with its ligands. Whether Siglec‐E expression on macrophages impacts foam cell formation and atherosclerosis remains to be established. To this end, both apoE‐deficient and apoE/Siglec‐E‐double deficient mice were placed on high fat diet for 3 months and their lipid profiles and severities of atherosclerosis were then assessed. The results showed that Siglec‐E deficiency accelerated atherosclerosis without affecting lipid profile in apoE deficient mice. In vitro experiments demonstrated that Siglec‐E deletion facilitated the uptake of acetylated or oxidized low density lipoprotein (LDL) and augmented foam cell formation in macrophages. By performing proximity labeling and proteomic analysis, we identified CD36 as a cell surface protein interacting with Siglec‐E. Notably, the interaction between Siglec‐E and CD36 was not affected by the sialylation status of CD36. Further experiments demonstrated that oxidized LDL induced transient Siglec‐E phosphorylation and recruitment of SHP‐1 in macrophages. VAV, a downstream effector implicated in CD36‐mediated oxidized LDL uptake, was shown to interact with SHP‐1 following oxidized LDL treatment. Moreover, Siglec‐E deficiency enhanced VAV phosphorylation induced by oxidized LDL. Collectively, these data demonstrate that Siglec‐E attenuates atherosclerosis in apoE‐deficient mice through suppressing CD36‐mediated signaling responsible for modified LDL uptake and foam cell formation in macrophages.