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TREM2 promotes cholesterol uptake and foam cell formation in atherosclerosis

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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.

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Data availability

All the data supporting the findings of this study are available within the paper. Data will be made available on reasonable request, not applicable for material.

Abbreviations

ApoE −/− :

Apolipoprotein E knockout

AS:

Atherosclerosis

BMDMs:

Bone marrow-derived macrophages

BODIPY:

4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene

CD36:

Cluster of differentiation 36 Deh dehydrocorydaline

DAPI:

4ʹ,6-diamidino-2-phenylindole

DEGs:

Differentially expressed genes

Deh:

Dehydrocorydaline

DiI-oxLDL:

Dil-labeled oxLDL

GEO:

Gene Expression Omnibus

HFD:

High-fat diet

IF:

Immunofluorescence

MAPK:

Mitogen-activated protein kinase

M-CSF:

Macrophage colony-stimulating factor

Mfi:

Mean fluorescence intensity

mSMCs:

Mouse primary aortic SMCs

ORO:

Oil Red O

OxLDL:

Oxidized low-density lipoprotein

p-ERK1/2:

Phosphorylated ERK1/2

p-JNK:

Phosphorylated JNK

p-p38:

Phosphorylated p38

PPARγ:

Peroxisome proliferator activated-receptor gamma

SMCs:

Vascular smooth muscle cells

t-ERK1/2:

Total ERK1/2

t-JNK:

Total JNK

t-p38:

Total p38

TREM2:

Triggering receptor expressed on myeloid cells 2

α-SMA:

α-Smooth muscle actin

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Acknowledgements

We thank the Central Laboratory of Union Hospital of Tongji Medical College for providing a confocal microscope and flow cytometer.

Funding

This work was supported by the National Natural Science Foundation of China (no. 81974182 and no. 82171325 to LM).

Author information

Author notes

  1. Xiaoqing Guo and Bowei Li contributed equally to this article.

Authors and Affiliations

  1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Xiaoqing Guo, Bowei Li, Cheng Wen, Feng Zhang, Xuying Xiang, Lei Nie, Jiaojiao Chen & Ling Mao

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  1. Xiaoqing Guo
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  2. Bowei Li
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  3. Cheng Wen
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  4. Feng Zhang
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  5. Xuying Xiang
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  6. Lei Nie
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  7. Jiaojiao Chen
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  8. Ling Mao
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Contributions

Conceptualization: LM; methodology: XG and BL; formal analysis and investigation: XG, CW, FZ, XX, LN, and JC; writing–original draft preparation: XG and BL; writing–review and editing: LM and XG; funding acquisition: LM.

Corresponding author

Correspondence to Ling Mao.

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Supplementary Information

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18_2023_4786_MOESM1_ESM.pdf

Supplementary file1Fig. S1 TREM2 has no significant effect on body weight, lipid profile or collagen deposition. a. Antibody specificity validation of TREM2 molecules (red) in Trem2−/− mice. Scale bar: 50 µm. Nuclei were stained with DAPI (blue). b, Genotyping of TREM2 gene knockout in mice. Average body weights (c) and lipid profiles (d) of Trem2+/+/ApoE−/− and Trem2−/−/ApoE−/− mice (n = 6/group, student’s t-test). e, The percentage of collagen content and the thickness of fibrous caps were assessed in Masson staining images. Scale bar: 200 μm (n = 6/group, student’s t-test). *P < 0.05; ns, P > 0.05 (PDF 4323 KB)

18_2023_4786_MOESM2_ESM.pdf

Supplementary file2Fig. S2 TREM2 deficiency decreases CD36 expression. a, PCR-detected lentivirus overexpressing TREM2 in RAW264.7 cells and mSMCs (n = 6-7/group, student’s t-test). b, TREM2 stimulates primary BMDM foam cell formation. BMDMs isolated from Trem2+/+ and Trem2−/− mice were stimulated with oxLDL at 50 µg/mL for 24 h. Then the cells were incubated with BODIPY in DMEM for 1 h. A flow analyzer evaluated the mFI of the two groups of cells (n = 3/group, student’s t-test). c, Quantitative real-time PCR analysis of the mRNA levels of MSR1, OLR1, ABCA1 and ABCG1 in macrophages and mSMCs in the LV-GFP or LV-TREM2 group. Data are normalized to ACTB expression (n = 6/group, student’s t-test). d, Relative expression of CD36 (green) at the aortic sinus in Trem2+/+/ApoE−/− and Trem2−/−/ApoE−/− mice by immunofluorescence (n = 4/group, student’s t-test). Scale bar: 50 µm. e, Quantitative real-time PCR analysis of the mRNA levels of CD36 in primary BMDMs and mSMCs isolated from Trem2+/+ and Trem2−/− mice (n = 4/group, student’s t-test). *P < 0.05, **P < 0.01, ****P < 0.0001; ns, P > 0.05; mFI, mean fluorescence intensity (PDF 1510 KB)

18_2023_4786_MOESM3_ESM.pdf

Supplementary file3Fig. S3 Knockout of the TREM2 gene inhibits lipid uptake. a, Flow analysis showed the mFI of BMDMs isolated from Trem2+/+ and Trem2−/− mice stimulated with DiI-oxLDL at 10 µg/mL for 4 h (n = 3/group, student’s t-test). b, WB and PCR levels of CD36 expression in macrophages and mSMCs transfected with the control vector (NC) or the CD36 siRNA (siCD36, n = 4-6/group, student’s t-test). *P < 0.05, **P < 0.01, ****P < 0.0001; mFI, mean fluorescence intensity (PDF 123 KB)

Supplementary file4 (DOCX 27 KB)

Supplementary file5 (DOCX 25 KB)

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Guo, X., Li, B., Wen, C. et al. TREM2 promotes cholesterol uptake and foam cell formation in atherosclerosis. Cell. Mol. Life Sci. 80, 137 (2023). https://doi.org/10.1007/s00018-023-04786-9

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