TREM2 promotes cholesterol uptake and foam cell formation in atherosclerosis.

Abstract

Disordered lipid accumulation in the arterial wall is a hallmark of atherosclerosis. Previous studies found that the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane receptor of the immunoglobulin family, is increased in mouse atherosclerotic aortic plaques. However, it remains unknown whether TREM2 plays a role in atherosclerosis. Here we investigated the role of TREM2 in atherosclerosis using ApoE knockout (ApoE-/-) mouse models, primary vascular smooth muscle cells (SMCs), and bone marrow-derived macrophages (BMDMs). In ApoE-/- mice, the density of TREM2-positive foam cells in aortic plaques increased in a time-dependent manner after the mice were fed a high-fat diet (HFD). Compared with ApoE-/- mice, the Trem2-/-/ApoE-/- double-knockout mice showed significantly reduced atherosclerotic lesion size, foam cell number, and lipid burden degree in plaques after HFD feeding. Overexpression of TREM2 in cultured vascular SMCs and macrophages exacerbates lipid influx and foam cell formation by upregulating the expression of the scavenger receptor CD36. Mechanistically, TREM2 inhibits the phosphorylation of p38 mitogen-activated protein kinase and peroxisome proliferator activated-receptor gamma (PPARγ), thereby increasing PPARγ nuclear transcriptional activity and subsequently promoting the transcription of CD36. Our results indicate that TREM2 exacerbates atherosclerosis development by promoting SMC- and macrophage-derived foam cell formation by regulating scavenger receptor CD36 expression. Thus, TREM2 may act as a novel therapeutic target for the treatment of atherosclerosis.

• Authors: Xiaoqing Guo, Bowei Li, Cheng Wen, Feng Zhang, Xuying Xiang, Lei Nie, Jiaojiao Chen, Ling Mao
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 80 Issue 5 Pg. 137 (May 03 2023) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 37133566 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Chemical References

• PPAR gamma
• CD36 Antigens
• Cholesterol
• Apolipoproteins E
• Lipids
• Lipoproteins, LDL
• Trem2 protein, mouse
• Membrane Glycoproteins
• Receptors, Immunologic

Topics

• Mice
• Animals
• Foam Cells (metabolism, pathology)
• PPAR gamma (genetics, metabolism)
• Atherosclerosis (metabolism)
• Plaque, Atherosclerotic (metabolism)
• Mice, Knockout
• CD36 Antigens (genetics, metabolism)
• Cholesterol (metabolism)
• Apolipoproteins E (genetics, metabolism)
• Lipids
• Lipoproteins, LDL (metabolism)
• Membrane Glycoproteins (genetics, metabolism)
• Receptors, Immunologic (genetics, metabolism)