TREM2

The TREM2 gene lies on the sixth chromosome in humans, specifically in location 6p21.1. The gene has 5 coding exon regions. Alternative splicing of the TREM2 mRNA transcript leads to different isoforms of the protein being produced upon translation. TREM2 mRNA is most highly expressed in brain, lungs, adrenal glands, placenta, gall bladder, and colon. TREM2 orthologs are also present in rat, dog, Rhesus monkey, macaque, chimpanzee, and other animals. == Structure ==

The TREM2 receptor is a transmembrane protein that is made up of an extracellular region (also referred to as the ectodomain), the membrane-traversing segment, and an intracellular component. The extracellular component of TREM2 can bind different anionic ligands, specifically glycoproteins and lipids. This ectodomain component includes an Ig-like V-type domain, where ligands bind the receptor. The TREM2 ectodomain is modified after protein translation; these modifications affect its affinity for different ligands. The intracellular component of TREM2 does not have any signaling ability on its own; rather, it signals via the DNAX activator proteins 10 and 12 (DAP10 and DAP12). A single TREM2 molecule can interact with DAP10 and DAP12 at the same time. Part of the ectodomain of TREM2 can be processed by enzymes (ADAM10, ADAM17) and released as a soluble version, called soluble TREM2 (sTREM2). This protein fragment is released into the serum and cerebral spinal fluid (CSF), and might serve as a biomarker for neurodegenerative and other disorders, but further studies are needed. == Function ==

. Image available through RCSB PDB. The TREM2 protein is found in immune cells termed myeloid cells, which include macrophages, granulocytes, monocytes, and dendritic cells. Monocyte-, macrophage-, and neutrophil-mediated inflammatory responses can be stimulated through G protein-linked 7-transmembrane receptors (e.g., FPR1), Fc receptors, CD14, toll like receptors (such as TLR4), and cytokine receptors (e.g., IFNGR1). Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to the immunoglobulin (Ig) superfamily, such as TREM2, or to the C-type lectin superfamily. On myeloid cells, TREM2 binds anionic molecules, free and bound to plasma membrane, including bacterial products, DNA, lipoproteins, phospholipids, glycoproteins, DNA, and bacterial fragments. TREM2 binding of ligand results in phosphorylation at 2 tyrosines in the immunoreceptor tyrosine-based activation motif (ITAM) of DAP12 by SRC tyrosine kinases. Association of TREM2 with DAP10 also activates the PI3K signaling pathway, leading to expression of transcription factors that include AP1, NF-κB, and NFAT. and osteoclasts, and is involved in development and/or maintenance of brain and bone. In brain, the highest levels of TREM2 are found in hippocampus, white matter, and the spinal cord, and levels of TREM2 increase with age in humans and mice. TREM2 signaling leads to downregulated transcription of genes that promote inflammation (Tnf, Il1b, and Nos2), as well as release of cytokines that prevent activation of anti-tumor CD8+ T cells. TREM2+ immunosuppressive TAMs correlate with the level of exhausted T cells in the human tumor microenvironment (TME). A TREM2+ TAM-rich TME therefore appears to be immune suppressive and might promote resistance to cancer therapies, such as checkpoint inhibitors. TREM2 signaling can antagonize TLR expression and signaling, resulting in reduced production of inflammatory cytokines by cultured mouse macrophages. The neuroprotective effects of TREM2 involve not only production of anti-inflammatory cytokines, but also clearance of abnormal proteins and phagocytosis of apoptotic neurons. sTREM might therefore have pro-inflammatory effects. Levels of sTREM2 are increased in CSF of patients with Alzheimer's disease, and correlate with the CSF levels of disease biomarkers, such as t-tau and p-tau. == Clinical significance ==

TREM2 signaling has been associated with pathogenesis of several diseases. Variants of in the DAP12 (TYROBP) or TREM2 genes have been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL or Nasu–Hakola disease). Alzheimer's disease Missense variants of TREM2, most prominently R47H, increase the risk for Alzheimer's disease (AD). TREM2 is involved in the microglial response to the amyloid plaques that are characteristic of AD. Loss of TREM2 function reduces the responses of microglia to plaques, thought to increase plaque toxicity and damage to neurites. Cancer Although TREM2 expression is low in most normal tissues, it is overexpressed in many human tumor types. An analysis of levels of TREM2 mRNA in 33 cancer tissues from The Cancer Genome Atlas (TCGA) indicate higher levels of expression in tumor vs normal tissues in 18 cancer types, including head and neck squamous cell carcinoma, colon adenocarcinoma, and glioblastoma, as well as gynecologic, liver, gastric, kidney, breast, bladder, and esophageal cancers. TREM2+ macrophages from human tumors also express CD68, CD163, CSF1R, and nuclear MAFB. IBD TREM2 expressed by human monocyte dendritic cells Expression of TREM2 is limited to inflamed sections of intestine and contribute to IBD development. Mice with disruption of Trem2 had more severe liver damage following administration of carbon tetrachloride or acetaminophen, compared to mice without gene disruption. The authors of this study found that TREM2 is expressed by Kupfer cells and hepatic stellate cells, indicating that TREM2 might downregulate inflammation. This study also showed that disruption of Trem2 promoted tumor development and exacerbated liver damage and inflammation. In liver tumors, TREM2 was expressed by tumor-infiltrating macrophages (TAMs). TREM2 might therefore promote the resolution of inflammation during hepatic injury, ultimately preventing parenchymal cell death. PLOSL or Nasu–Hakola disease PLOSL or Nasu–Hakola disease is a neurodegenerative disorder characterized by bone cysts, dementia, and early death and is associated with variants in the TYROBP gene (encodes DAP12 protein) and TREM2 gene. Several recessive, inactivating mutations in TREM2 and TYROBP (encodes DAP12 protein) have been identified that can cause PLOSL. The mutations prevent association between TREM2 and DAP12 or expression of shorter, non-functional forms of TREM2. Other diseases TREM2 has also been linked to additional disorders such as ALS, Parkinson's disease, and more dementia related conditions. == As a drug target ==

TREM2 is a good therapeutic target for several diseases, including cancer and liver and neurodegenerative diseases. Several companies are developing agents to target TREM2. However, TREM2 is likely to have distinct roles in the pathogenesis of these disorders, so therapeutic agents in development employ different approaches to modify TREM2 activity. Neurodegenerative diseases In the brain, TREM2 is expressed on microglia that regulate clearance of neuronal debris. Variants of TREM2 that encode proteins with reduced affinity for ligands have been associated with Alzheimer's disease. Targeting sTREM2 A potential mechanism of intervention could be targeting the enzymes that cleave the ectodomain, adjusting the rate at which sTREM2 is released. In rodents, a potential therapeutic using this mechanism was used against AD pathology, and the rodents had smaller plaques than controls. == References ==