Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Nov 4;12(1):131.
doi: 10.1186/s40364-024-00675-w.

The double-edged role and therapeutic potential of TREM2 in atherosclerosis

Botao Zhu  1 , Yuxuan Liu  1 , Daoquan Peng  2
Affiliations
Review

The double-edged role and therapeutic potential of TREM2 in atherosclerosis

Botao Zhu et al. Biomark Res. .

Abstract

Atherosclerosis is a chronic lipid-driven inflammatory disease characterized by infiltration of large numbers of macrophages. The progression of the disease is closely related to the status of macrophages in atherosclerotic plaques. Recent advances in plaque analysis have revealed a subpopulation of macrophages that express high levels of triggering receptor expressed on myeloid cells 2 (TREM2). Although TREM2 is known to play a critical role in inflammation, lipid metabolism, and tissue repair, its role in atherosclerosis is still not fully understood. Recent studies have shown that TREM2 promotes macrophage cholesterol uptake and efflux, enhances efferocytosis function, regulates inflammation and metabolism, and promotes cell survival, all of which are significant functions in atherosclerosis. In early plaques TREM2 promotes lipid uptake and increases lesion size. In advanced plaques TREM2 promotes macrophage survival and increases plaque stability. The dualistic nature of TREM2 in atherosclerosis, where it can exert both protective effect and a side effect of increased lesion size, presents a complex but crucial area of study. Understanding these dual roles could help in the development of new therapeutic strategies to modulate TREM2 activity and utilize its atheroprotective function while mitigating its deleterious effects. In this review, we discuss the roles and mechanisms of TREM2 during different stages of atherosclerotic plaques, as well as the potential applications of TREM2 in the diagnosis and treatment of atherosclerosis.

Keywords: Atherosclerosis; Macrophage; Plaque stability; TREM2; Therapeutic strategies.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Structural features and basic functions of triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 consists of an extracellular domain, a separate transmembrane domain, and a short cytoplasmic domain that does not have any signaling function. TREM2 binds to the DNAX activating protein 12 (DAP12) protein via the transmembrane domain. Triggered by TREM2, the activation motif of the immunoreceptor tyrosine (ITAM) in the cytoplasmic domain of DAP12 is phosphorylated by members of the SRC kinase family. The phosphorylated ITAM recruits the protein tyrosine kinase (SYK) to activate phosphatidylinositol 3-kinase (PI3K) and phospholipase Cγ2 (PLCγ2). Activated by PI3K, the kinase AKT supports protein synthesis and energy metabolism by activating the mechanistic _target of rapamycin (mTOR) pathway. AKT can inactivate glycogen synthase kinase 3β (GSK3β) by stabilizing β-cyclin, contributing to cell survival and proliferation. PLCγ2 catalyzes the degradation of phosphatidylinositol 4,5-bisphosphate (Ptdlns(4,5)P2) to inositol 1,4,5-trisphosphate (InsP(3)Rs) and diacylglycerol (DAG). InsP(3)Rs induces intracellular Ca2+ mobilization. TREM2 can also inhibit the activation of Toll-like receptors (TLRs), which are capable of activating NF-κB. The α-secretases disintegrin and metalloproteinase-17 (ADAM17) and ADAM10 can cleave the extracellular domain of TREM2 at the H157-S158 peptide bond, which releases soluble TREM2 (sTREM2)
Fig. 2
Fig. 2
The role and mechanism of triggering receptor expressed on myeloid cells 2 (TREM2) in atherosclerosis. In early plaques, TREM2 increases lesion size because TREM2 promotes the expression of CD36, which is associated with lipid uptake, by increasing peroxisome proliferator-activated receptor gamma (PPARγ) activation. Additionally, TREM2 promotes cholesterol efflux by activating liver X receptor (LXR) and upregulating the expression of ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1), which reduces endoplasmic reticulum (ER) stress and helps to maintain the survival of cells. The increased survival of macrophages results in relatively greater uptake of lipids. However, in advanced atherosclerotic plaques, TREM2 plays a protective role by enhancing macrophage efferocytosis function and modulating inflammation, which reduces the risk of plaque necrotic core formation and rupture. TREM2 can inhibit Toll-like receptor (TLR) induced amplification of inflammatory signals. When treated with TREM2 agonists, the metabolism of foamy macrophages was reprogrammed to oxidative phosphorylation (OXPHOS), promoting cell survival. Macrophage survival in advanced plaques would contribute to plaque stabilization. ox-LDL indicates oxidized low-density lipoprotein
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global Burden of Cardiovascular diseases and Risk factors, 1990–2019: Update from the GBD 2019 study. J Am Coll Cardiol. 2020;76:2982–3021. 10.1016/j.jacc.2020.11.010. - PMC - PubMed
    1. Libby P. The changing landscape of atherosclerosis. Nature. 2021;592:524–33. 10.1038/s41586-021-03392-8. - PubMed
    1. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Reviews Disease Primers. 2019;5. 10.1038/s41572-019-0106-z. - PubMed
    1. Luo Y, Duan H, Qian Y, Feng L, Wu Z, Wang F, et al. Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis. Cell Res. 2017;27:352–72. 10.1038/cr.2017.8. - PMC - PubMed
    1. Chen W, Schilperoort M, Cao Y, Shi J, Tabas I, Tao W. Macrophage-_targeted nanomedicine for the diagnosis and treatment of atherosclerosis. Nat Rev Cardiol. 2022;19:228–49. 10.1038/s41569-021-00629-x. - PMC - PubMed

LinkOut - more resources

  NODES
twitter 2