Abstract

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.Support or Funding InformationThis work was supported by a grant from Ministry of Science and Technology of Taiwan (MOST‐106‐2320‐B‐001‐020‐MY3).

Highlights

  • The accumulation of lipid-laden macrophages, foam cells, within sub-endothelial intima is a key feature of early atherosclerosis

  • By performing proximity labeling and proteomic analy‐ sis, we identified scavenger receptor CD36 as a cell surface protein interacting with Siglec-E

  • Further experiments performed in HEK293T cells transiently overexpressing Siglec-E and CD36 and peritoneal macrophages demonstrated that depletion of cell surface sialic acids by treatment with sialyltransferase inhibitor or sialidase did not affect interac‐ tion between Siglec-E and CD36 but retarded Siglec-E-mediated inhibition on oxidized low-density lipoprotein (LDL) uptake

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Summary

Introduction

The accumulation of lipid-laden macrophages, foam cells, within sub-endothelial intima is a key feature of early atherosclerosis. The monocytes differentiate into macrophages and uptake modified LDLs to become foam cells with a feature of intracellular cholesterol accumulation as lipid droplets, which is the hallmark of early lesion [2,3,4] These foam cells in turn produce more inflammatory cytokines and growth factors to promote the migration of the quiescent vascular smooth muscle cells (VSMCs) in the medial layer to intima and activate VSMC proliferation and increased synthesis of extracellular matrix proteins, resulting in the thickening of intima and occlusion of the blood vessel [2,3,4]. At the advanced stage foam cells are unable to fully process the internalized cholesterol and eventually die, causing the deposition of cholesterol and the formation of lipid necrotic core in the arterial wall This triggers further immune reaction to exacerbate the disease progression and provoke coronary rupture underlying heart attack [2,3,4]. It is apparent that macrophage-derived foam cells play a key role in the initiation and progression of atherosclerosis

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