TREM2

The [https://www.ncbi.nlm.nih.gov/gene/54209 TREM2] gene lies on the sixth chromosome in humans, specifically in location 6p21.1. The gene has 5 coding exon regions.{{Cite web|title=TREM2 triggering receptor expressed on myeloid cells 2 [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/54209|access-date=2021-11-02|website=www.ncbi.nlm.nih.gov}}{{cite journal | vauthors = Natale G, Biagioni F, Busceti CL, Gambardella S, Limanaqi F, Fornai F | title = TREM Receptors Connecting Bowel Inflammation to Neurodegenerative Disorders | journal = Cells | volume = 8 | issue = 10 | pages = E1124 | date = September 2019 | pmid = 31546668 | pmc = 6829526 | doi = 10.3390/cells8101124 | doi-access = free }} Alternative splicing of the TREM2 mRNA transcript leads to different isoforms of the protein being produced upon translation. Specifically, TREM2 mRNA has 3 different isoforms containing 3 consistent exons, and 2 that vary between the isoforms.{{cite journal | vauthors = Yang J, Fu Z, Zhang X, Xiong M, Meng L, Zhang Z | title = TREM2 ectodomain and its soluble form in Alzheimer's disease | journal = Journal of Neuroinflammation | volume = 17 | issue = 1 | pages = 204 | date = July 2020 | pmid = 32635934 | pmc = 7341574 | doi = 10.1186/s12974-020-01878-2 | doi-access = free }} TREM2 mRNA is most highly expressed in brain, lungs, adrenal glands, placenta, gall bladder, and colon. The functions of TREM2 have been studied in mice with disruption or mutation of the mouse ortholog, [https://www.ncbi.nlm.nih.gov/gene/83433 Trem2].{{Cite web|title=Jackson Laboratory Search- TREM2|url=https://www.jax.org/search?q=trem2&filter=Url%3A(%22%2Fjax-mice-and-services%22%20OR%20%22https%3A%2F%2Fresources.jax.org%22)%20OR%20Author%3A%22JMCRS%22 |website=Jackson Laboratory}} [https://www.ncbi.nlm.nih.gov/gene/54209/ortholog/ TREM2 orthologs] are also present in rat, dog, Rhesus monkey, macaque, chimpanzee, and other animals.{{cite journal | vauthors = Smith JR, Hayman GT, Wang SJ, Laulederkind SJ, Hoffman MJ, Kaldunski ML, Tutaj M, Thota J, Nalabolu HS, Ellanki SL, Tutaj MA, De Pons JL, Kwitek AE, Dwinell MR, Shimoyama ME | display-authors = 6 | title = The Year of the Rat: The Rat Genome Database at 20: a multi-species knowledgebase and analysis platform | journal = Nucleic Acids Research | volume = 48 | issue = D1 | pages = D731–D742 | date = January 2020 | pmid = 31713623 | pmc = 7145519 | doi = 10.1093/nar/gkz1041 }}

File:STREM2-2.jpg

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.{{cite journal | vauthors = Kulkarni B, Kumar D, Cruz-Martins N, Sellamuthu S | title = Role of TREM2 in Alzheimer's Disease: A Long Road Ahead | journal = Molecular Neurobiology | volume = 58 | issue = 10 | pages = 5239–5252 | date = October 2021 | pmid = 34275100 | doi = 10.1007/s12035-021-02477-9 | s2cid = 236090999 }} The extracellular component of TREM2 can bind different anionic ligands, specifically glycoproteins and lipids.{{cite journal | vauthors = Hamerman JA, Pottle J, Ni M, He Y, Zhang ZY, Buckner JH | title = Negative regulation of TLR signaling in myeloid cells--implications for autoimmune diseases | journal = Immunological Reviews | volume = 269 | issue = 1 | pages = 212–227 | date = January 2016 | pmid = 26683155 | pmc = 4703580 | doi = 10.1111/imr.12381 }}{{cite journal | vauthors = Deczkowska A, Weiner A, Amit I | title = The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway | journal = Cell | volume = 181 | issue = 6 | pages = 1207–1217 | date = June 2020 | pmid = 32531244 | doi = 10.1016/j.cell.2020.05.003 | s2cid = 219572314 | doi-access = free }} This ectodomain component includes an Ig-like V-type domain, where ligands bind the receptor.{{cite journal | vauthors = Dardiotis E, Siokas V, Pantazi E, Dardioti M, Rikos D, Xiromerisiou G, Markou A, Papadimitriou D, Speletas M, Hadjigeorgiou GM | display-authors = 6 | title = A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature | journal = Neurobiology of Aging | volume = 53 | pages = 194.e13–194.e22 | date = May 2017 | pmid = 28214109 | doi = 10.1016/j.neurobiolaging.2017.01.015 | s2cid = 22618858 }} 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.

File:5eli_assembly-1.jpg. Image available through RCSB PDB.{{cite journal | vauthors = Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ | title = Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms | journal = eLife | volume = 5 | pages = e20391 | date = December 2016 | pmid = 27995897 | pmc = 5173322 | doi = 10.7554/eLife.20391 | doi-access = free }}]]

The TREM2 protein is found in immune cells termed myeloid cells, which include macrophages, granulocytes, monocytes, and dendritic cells.{{cite journal | vauthors = De Kleer I, Willems F, Lambrecht B, Goriely S | title = Ontogeny of myeloid cells | journal = Frontiers in Immunology | volume = 5 | pages = 423 | date = 2014 | pmid = 25232355 | pmc = 4153297 | doi = 10.3389/fimmu.2014.00423 | doi-access = free }} 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).{{cite journal | vauthors = Futosi K, Fodor S, Mócsai A | title = Neutrophil cell surface receptors and their intracellular signal transduction pathways | journal = International Immunopharmacology | volume = 17 | issue = 3 | pages = 638–650 | date = November 2013 | pmid = 23994464 | pmc = 3827506 | doi = 10.1016/j.intimp.2013.06.034 }}{{cite journal | vauthors = Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L | display-authors = 6 | title = Inflammatory responses and inflammation-associated diseases in organs | journal = Oncotarget | volume = 9 | issue = 6 | pages = 7204–7218 | date = January 2018 | pmid = 29467962 | pmc = 5805548 | doi = 10.18632/oncotarget.23208 }} 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.{{cite journal | vauthors = Sancho D, Reis e Sousa C | title = Sensing of cell death by myeloid C-type lectin receptors | journal = Current Opinion in Immunology | volume = 25 | issue = 1 | pages = 46–52 | date = February 2013 | pmid = 23332826 | pmc = 4480265 | doi = 10.1016/j.coi.2012.12.007 }}

On myeloid cells, TREM2 binds anionic molecules, free and bound to plasma membrane, including bacterial products, DNA, lipoproteins, phospholipids, glycoproteins, DNA, and bacterial fragments.{{cite journal | vauthors = Kober DL, Brett TJ | title = TREM2-Ligand Interactions in Health and Disease | journal = Journal of Molecular Biology | volume = 429 | issue = 11 | pages = 1607–1629 | date = June 2017 | pmid = 28432014 | pmc = 5485854 | doi = 10.1016/j.jmb.2017.04.004 }}{{cite journal | vauthors = Kober DL, Brett TJ | title = TREM2-Ligand Interactions in Health and Disease | journal = Journal of Molecular Biology | volume = 429 | issue = 11 | pages = 1607–1629 | date = June 2017 | pmid = 28432014 | pmc = 5485854 | doi = 10.1016/j.jmb.2017.04.004 }} TREM2 binding of ligand results in phosphorylation at 2 tyrosines in the immunoreceptor tyrosine-based activation motif (ITAM) of DAP12 by SRC tyrosine kinases. Spleen tyrosine kinase (Syk) interacts with these phosphorylation sites and activates the phosphatidylinositol-3 kinase (PI3K) signaling pathway, as well as other signaling molecules such as mTOR, MAPK, and ERK.{{cite journal | vauthors = Xing J, Titus AR, Humphrey MB | title = The TREM2-DAP12 signaling pathway in Nasu-Hakola disease: a molecular genetics perspective | journal = Research and Reports in Biochemistry | volume = 5 | pages = 89–100 | date = 2015 | pmid = 26478868 | pmc = 4605443 | doi = 10.2147/RRBC.S58057 | doi-access = free }} Association of TREM2 with DAP10 also activates the PI3K signaling pathway,{{cite journal | vauthors = Qiu H, Shao Z, Wen X, Jiang J, Ma Q, Wang Y, Huang L, Ding X, Zhang L | display-authors = 6 | title = TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy | journal = Frontiers in Immunology | volume = 12 | pages = 716710 | date = 2021 | pmid = 34539652 | pmc = 8446424 | doi = 10.3389/fimmu.2021.716710 | doi-access = free }} leading to expression of transcription factors that include AP1, NF-κB, and NFAT. The PI3K signaling pathway also increases intracellular calcium content, which activates calcium-dependent kinases. TREM2 activation also affects expression of GAL1, GAL3, IL1RN, and progranulin, which modulate the immune response.

TREM2 is expressed by microglia{{cite journal |vauthors=Gratuze M, Leyns CE, Holtzman DM |date=December 2018 |title=New insights into the role of TREM2 in Alzheimer's disease |journal=Molecular Neurodegeneration |volume=13 |issue=1 |pages=66 |doi=10.1186/s13024-018-0298-9 |pmc=6302500 |pmid=30572908 |doi-access=free }} and osteoclasts, and is involved in development and/or maintenance of brain and bone. In mice, TREM2 is involved in synaptic pruning, a process of shaping neuronal circuitry by microglia- and astrocyte-mediated removal of excessive synapses via phagocytosis.{{cite journal | vauthors = Hong S, Dissing-Olesen L, Stevens B | title = New insights on the role of microglia in synaptic pruning in health and disease | journal = Current Opinion in Neurobiology | volume = 36 | pages = 128–134 | date = February 2016 | pmid = 26745839 | pmc = 5479435 | doi = 10.1016/j.conb.2015.12.004 }}{{cite journal | vauthors = Filipello F, Morini R, Corradini I, Zerbi V, Canzi A, Michalski B, Erreni M, Markicevic M, Starvaggi-Cucuzza C, Otero K, Piccio L, Cignarella F, Perrucci F, Tamborini M, Genua M, Rajendran L, Menna E, Vetrano S, Fahnestock M, Paolicelli RC, Matteoli M | display-authors = 6 | title = The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity | journal = Immunity | volume = 48 | issue = 5 | pages = 979–991.e8 | date = May 2018 | pmid = 29752066 | doi = 10.1016/j.immuni.2018.04.016 | s2cid = 21700781 | doi-access = free }} 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 is also expressed by macrophages of adipose tissue, adrenal gland, and placenta.

Immunosuppressive tumor-associated macrophages (TAMs) have been characterized by expression of TREM2.{{cite journal | vauthors = Molgora M, Colonna M | title = Turning enemies into allies-reprogramming tumor-associated macrophages for cancer therapy | journal = Med | volume = 2 | issue = 6 | pages = 666–681 | date = June 2021 | pmid = 34189494 | pmc = 8238417 | doi = 10.1016/j.medj.2021.05.001 }} TREM2 signaling leads to downregulated transcription of genes that promote inflammation (Tnf, Il1b, and Nos2),{{cite journal | vauthors = Takahashi K, Rochford CD, Neumann H | title = Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2 | journal = The Journal of Experimental Medicine | volume = 201 | issue = 4 | pages = 647–657 | date = February 2005 | pmid = 15728241 | pmc = 2213053 | doi = 10.1084/jem.20041611 }} as well as release of cytokines that prevent activation of anti-tumor CD8⁺ T cells.{{cite journal | vauthors = Molgora M, Esaulova E, Vermi W, Hou J, Chen Y, Luo J, Brioschi S, Bugatti M, Omodei AS, Ricci B, Fronick C, Panda SK, Takeuchi Y, Gubin MM, Faccio R, Cella M, Gilfillan S, Unanue ER, Artyomov MN, Schreiber RD, Colonna M | display-authors = 6 | title = TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy | journal = Cell | volume = 182 | issue = 4 | pages = 886–900.e17 | date = August 2020 | pmid = 32783918 | pmc = 7485282 | doi = 10.1016/j.cell.2020.07.013 }} TREM2⁺ immunosuppressive TAMs correlate with the level of exhausted T cells in the human tumor microenvironment (TME).{{cite journal | vauthors = Binnewies M, Pollack JL, Rudolph J, Dash S, Abushawish M, Lee T, Jahchan NS, Canaday P, Lu E, Norng M, Mankikar S, Liu VM, Du X, Chen A, Mehta R, Palmer R, Juric V, Liang L, Baker KP, Reyno L, Krummel MF, Streuli M, Sriram V | display-authors = 6 | title = Targeting TREM2 on tumor-associated macrophages enhances immunotherapy | journal = Cell Reports | volume = 37 | issue = 3 | pages = 109844 | date = October 2021 | pmid = 34686340 | doi = 10.1016/j.celrep.2021.109844 | s2cid = 239472808 | doi-access = free }} 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. Conversely, TREM2 expression is reduced following inflammatory signaling induction by lipopolysaccharide (a TLR4 ligand) or interferon gamma ([https://www.ncbi.nlm.nih.gov/gene/3458 IFNG]).{{cite journal | vauthors = Gao X, Dong Y, Liu Z, Niu B | title = Silencing of triggering receptor expressed on myeloid cells-2 enhances the inflammatory responses of alveolar macrophages to lipopolysaccharide | journal = Molecular Medicine Reports | volume = 7 | issue = 3 | pages = 921–926 | date = March 2013 | pmid = 23314916 | doi = 10.3892/mmr.2013.1268 | doi-access = free }} The neuroprotective effects of TREM2 involve not only production of anti-inflammatory cytokines, but also clearance of abnormal proteins and phagocytosis of apoptotic neurons.

In contrast to anti-inflammatory effects in brain and cancer, TREM2 signaling has been reported to contribute to intestinal inflammation and development of inflammatory bowel diseases (IBD). sTREM2 is believed to negatively regulate TREM2 signaling by acting as decoy receptors.{{cite journal | vauthors = Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, Rinker J, Naismith RT, Panina-Bordignon P, Passini N, Galimberti D, Scarpini E, Colonna M, Cross AH | display-authors = 6 | title = Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation | journal = Brain | volume = 131 | issue = Pt 11 | pages = 3081–3091 | date = November 2008 | pmid = 18790823 | pmc = 2577803 | doi = 10.1093/brain/awn217 }} sTREM might therefore have pro-inflammatory effects. sTREM2 has been indicated in activating signaling pathways such as PI3K and ERK through an unidentified receptor.{{cite journal | vauthors = Konishi H, Kiyama H | title = Microglial TREM2/DAP12 Signaling: A Double-Edged Sword in Neural Diseases | journal = Frontiers in Cellular Neuroscience | volume = 12 | pages = 206 | date = 2018 | pmid = 30127720 | pmc = 6087757 | doi = 10.3389/fncel.2018.00206 | doi-access = free }} 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.{{cite journal | vauthors = Yang J, Fu Z, Zhang X, Xiong M, Meng L, Zhang Z | title = TREM2 ectodomain and its soluble form in Alzheimer's disease | journal = Journal of Neuroinflammation | volume = 17 | issue = 1 | pages = 204 | date = July 2020 | pmid = 32635934 | pmc = 7341574 | doi = 10.1186/s12974-020-01878-2 | doi-access = free }}

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).{{cite journal | vauthors = Bianchin MM, Capella HM, Chaves DL, Steindel M, Grisard EC, Ganev GG, da Silva Júnior JP, Neto Evaldo S, Poffo MA, Walz R, Carlotti Júnior CG, Sakamoto AC | display-authors = 6 | title = Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy--PLOSL): a dementia associated with bone cystic lesions. From clinical to genetic and molecular aspects | journal = Cellular and Molecular Neurobiology | volume = 24 | issue = 1 | pages = 1–24 | date = February 2004 | pmid = 15049507 | doi = 10.1023/b:cemn.0000012721.08168.ee | s2cid = 7089775 | pmc = 11529946 }}

File:TREM2_Alzheimer's.jpg

Variants of TREM2 have been associated with neurodegenerative disorders, including Alzheimer's disease.{{cite journal | vauthors = Shi Y, Holtzman DM | title = Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight | journal = Nature Reviews. Immunology | volume = 18 | issue = 12 | pages = 759–772 | date = December 2018 | pmid = 30140051 | pmc = 6425488 | doi = 10.1038/s41577-018-0051-1 }} 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, which then appear to take on a more toxic state. Expression of TREM2 is associated with that of CD33.{{cite journal | vauthors = Griciuc A, Patel S, Federico AN, Choi SH, Innes BJ, Oram MK, Cereghetti G, McGinty D, Anselmo A, Sadreyev RI, Hickman SE, El Khoury J, Colonna M, Tanzi RE | display-authors = 6 | title = TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease | journal = Neuron | volume = 103 | issue = 5 | pages = 820–835.e7 | date = September 2019 | pmid = 31301936 | pmc = 6728215 | doi = 10.1016/j.neuron.2019.06.010 }}{{cite journal | vauthors = Chan G, White CC, Winn PA, Cimpean M, Replogle JM, Glick LR, Cuerdon NE, Ryan KJ, Johnson KA, Schneider JA, Bennett DA, Chibnik LB, Sperling RA, Bradshaw EM, De Jager PL | display-authors = 6 | title = CD33 modulates TREM2: convergence of Alzheimer loci | journal = Nature Neuroscience | volume = 18 | issue = 11 | pages = 1556–1558 | date = November 2015 | pmid = 26414614 | pmc = 4682915 | doi = 10.1038/nn.4126 }}{{Cite news| vauthors = Stetka B |date=2022-01-30|title=How a hyperactive cell in the brain might trigger Alzheimer's disease |language=en |work=NPR |url= https://www.npr.org/sections/health-shots/2022/01/30/1076166807/how-a-hyperactive-cell-in-the-brain-might-trigger-alzheimers-disease|access-date=2022-02-17}}

Zhong et al. reported that, in mice, stereotactic injection of sTREM2 or adeno-associated virus-mediated activation of sTREM2 reduced the amyloid plaque load and reduced functional memory deficits.{{cite journal | vauthors = Zhong L, Xu Y, Zhuo R, Wang T, Wang K, Huang R, Wang D, Gao Y, Zhu Y, Sheng X, Chen K, Wang N, Zhu L, Can D, Marten Y, Shinohara M, Liu CC, Du D, Sun H, Wen L, Xu H, Bu G, Chen XF | display-authors = 6 | title = Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model | journal = Nature Communications | volume = 10 | issue = 1 | pages = 1365 | date = March 2019 | pmid = 30911003 | pmc = 6433910 | doi = 10.1038/s41467-019-09118-9 | bibcode = 2019NatCo..10.1365Z }} Moreover, sTREM2 stimulated microglial proliferation and homing toward amyloid plaques where amyloid-β uptake and degradation was increased. Interestingly, these effects were specifically mediated by microglia. Level of sTREM2 in the CSF might be a biomarker for Alzheimer's disease and the associated inflammatory response.{{cite journal | vauthors = Liu D, Cao B, Zhao Y, Huang H, McIntyre RS, Rosenblat JD, Zhou H | title = Soluble TREM2 changes during the clinical course of Alzheimer's disease: A meta-analysis | journal = Neuroscience Letters | volume = 686 | pages = 10–16 | date = November 2018 | pmid = 30171911 | doi = 10.1016/j.neulet.2018.08.038 | s2cid = 52146124 }}{{cite journal | vauthors = Rauchmann BS, Schneider-Axmann T, Alexopoulos P, Perneczky R | title = CSF soluble TREM2 as a measure of immune response along the Alzheimer's disease continuum | journal = Neurobiology of Aging | volume = 74 | pages = 182–190 | date = February 2019 | pmid = 30458365 | pmc = 6331262 | doi = 10.1016/j.neurobiolaging.2018.10.022 }}{{cite journal | vauthors = Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C | display-authors = 6 | title = Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status | journal = Acta Neuropathologica | volume = 131 | issue = 6 | pages = 925–933 | date = June 2016 | pmid = 26754641 | pmc = 4867123 | doi = 10.1007/s00401-016-1533-5 }}

Although TREM2 expression is low in most normal tissues, it is overexpressed in many human tumor types.{{cite journal | vauthors = Cheng X, Wang X, Nie K, Cheng L, Zhang Z, Hu Y, Peng W | title = Systematic Pan-Cancer Analysis Identifies TREM2 as an Immunological and Prognostic Biomarker | journal = Frontiers in Immunology | volume = 12 | pages = 646523 | date = 2021 | pmid = 33679809 | pmc = 7925850 | doi = 10.3389/fimmu.2021.646523 | doi-access = free }} 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. High expression of TREM2 was associated with shorter survival times of patients with ovarian cancer, gastric cancer, lower-grade glioma, hepatocellular carcinoma, or [https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-kidney-tumors/clear-cell-renal-cell-carcinoma#:~:text=Clear%20cell%20renal%20cell%20carcinoma%2C%20or%20ccRCC%2C%20is%20a%20type,called%20conventional%20renal%20cell%20carcinoma. renal clear cell carcinoma]. Tumor infiltration by TREM2⁺, APOE⁺, C1q⁺ macrophage was reported to be a biomarker for recurrence of [https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-kidney-tumors/clear-cell-renal-cell-carcinoma#:~:text=Clear%20cell%20renal%20cell%20carcinoma%2C%20or%20ccRCC%2C%20is%20a%20type,called%20conventional%20renal%20cell%20carcinoma. clear-cell renal carcinoma].{{cite journal | vauthors = Binnewies M, Pollack JL, Rudolph J, Dash S, Abushawish M, Lee T, Jahchan NS, Canaday P, Lu E, Norng M, Mankikar S, Liu VM, Du X, Chen A, Mehta R, Palmer R, Juric V, Liang L, Baker KP, Reyno L, Krummel MF, Streuli M, Sriram V | display-authors = 6 | title = Targeting TREM2 on tumor-associated macrophages enhances immunotherapy | journal = Cell Reports | volume = 37 | issue = 3 | pages = 109844 | date = October 2021 | pmid = 34686340 | doi = 10.1016/j.celrep.2021.109844 | s2cid = 239472808 | doi-access = free }}{{cite journal | vauthors = Obradovic A, Chowdhury N, Haake SM, Ager C, Wang V, Vlahos L, Guo XV, Aggen DH, Rathmell WK, Jonasch E, Johnson JE, Roth M, Beckermann KE, Rini BI, McKiernan J, Califano A, Drake CG | display-authors = 6 | title = Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages | journal = Cell | volume = 184 | issue = 11 | pages = 2988–3005.e16 | date = May 2021 | pmid = 34019793 | pmc = 8479759 | doi = 10.1016/j.cell.2021.04.038 }} TREM2⁺ macrophages from human tumors also express CD68, CD163, CSF1R, and nuclear MAFB.{{cite journal | vauthors = Molgora M, Esaulova E, Vermi W, Hou J, Chen Y, Luo J, Brioschi S, Bugatti M, Omodei AS, Ricci B, Fronick C, Panda SK, Takeuchi Y, Gubin MM, Faccio R, Cella M, Gilfillan S, Unanue ER, Artyomov MN, Schreiber RD, Colonna M | display-authors = 6 | title = TREM2 Modulation Remodels the Tumor Myeloid Landscape Enhancing Anti-PD-1 Immunotherapy | journal = Cell | volume = 182 | issue = 4 | pages = 886–900.e17 | date = August 2020 | pmid = 32783918 | pmc = 7485282 | doi = 10.1016/j.cell.2020.07.013 }}

TREM2 expressed by human monocyte dendritic cells in the intestine.{{cite journal | vauthors = Stagg AJ | title = Intestinal Dendritic Cells in Health and Gut Inflammation | journal = Frontiers in Immunology | volume = 9 | pages = 2883 | date = 2018 | pmid = 30574151 | pmc = 6291504 | doi = 10.3389/fimmu.2018.02883 | doi-access = free }} Expression of TREM2 is limited to inflamed sections of intestine and contribute to IBD development. TREM2 is associated with increased production of inflammatory cytokines and changes in the gut microbiota.

One feature of liver disease is the initiation of an inflammatory process, leading to fibrosis and steatohepatitis. In mouse models of nonalcoholic steatohepatitis (NASH), disease development was associated with liver infiltration by monocyte-derived macrophages and increased expression of Trem2 and [https://www.ncbi.nlm.nih.gov/gene/12527 Cd9].{{cite journal | vauthors = Coelho I, Duarte N, Macedo MP, Penha-Gonçalves C | title = Insights into Macrophage/Monocyte-Endothelial Cell Crosstalk in the Liver: A Role for Trem-2 | journal = Journal of Clinical Medicine | volume = 10 | issue = 6 | pages = 1248 | date = March 2021 | pmid = 33802948 | pmc = 8002813 | doi = 10.3390/jcm10061248 | doi-access = free }} Mice with disruption of Trem2 had more severe liver damage following administration of carbon tetrachloride or acetaminophen, compared to mice without gene disruption.{{cite journal | vauthors = Perugorria MJ, Esparza-Baquer A, Oakley F, Labiano I, Korosec A, Jais A, Mann J, Tiniakos D, Santos-Laso A, Arbelaiz A, Gawish R, Sampedro A, Fontanellas A, Hijona E, Jimenez-Agüero R, Esterbauer H, Stoiber D, Bujanda L, Banales JM, Knapp S, Sharif O, Mann DA | display-authors = 6 | title = Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage | journal = Gut | volume = 68 | issue = 3 | pages = 533–546 | date = March 2019 | pmid = 29374630 | pmc = 6580759 | doi = 10.1136/gutjnl-2017-314107 }} The authors of this study found that TREM2 is expressed by Kupfer cells and hepatic stellate cells, indicating that TREM2 might downregulate inflammation. Expression was also increased in liver tissues from patients with cirrhosis. Compared with non-tumor liver tissue, TREM2 expression was increased in tumors from mice and patients with hepatocellular carcinoma (HCC).{{cite journal | vauthors = Esparza-Baquer A, Labiano I, Sharif O, Agirre-Lizaso A, Oakley F, Rodrigues PM, Zhuravleva E, O'Rourke CJ, Hijona E, Jimenez-Agüero R, Riaño I, Landa A, La Casta A, Zaki MY, Munoz-Garrido P, Azkargorta M, Elortza F, Vogel A, Schabbauer G, Aspichueta P, Andersen JB, Knapp S, Mann DA, Bujanda L, Banales JM, Perugorria MJ | display-authors = 6 | title = TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms | journal = Gut | volume = 70 | issue = 7 | pages = 1345–1361 | date = July 2021 | pmid = 32907830 | pmc = 8223629 | doi = 10.1136/gutjnl-2019-319227 }} This study also showed that disruption of Trem2 promoted tumor development and exacerbated liver damage and inflammation. In liver tumors, TREM2 was expressed by [https://jhoonline.biomedcentral.com/articles/10.1186/s13045-019-0760-3 tumor-infiltrating macrophages] (TAMs). TREM2 might therefore promote the resolution of inflammation during hepatic injury, ultimately preventing parenchymal cell death.

File:TREM2_NHD-2.jpg

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. Bone cysts in patients with PLOSL contain fat in lieu of bone marrow. In this disease, the main cell type in the brain that is affected is the microglia, where TREM2 is expressed.{{cite journal | vauthors = Mecca C, Giambanco I, Donato R, Arcuri C | title = Microglia and Aging: The Role of the TREM2-DAP12 and CX3CL1-CX3CR1 Axes | journal = International Journal of Molecular Sciences | volume = 19 | issue = 1 | pages = E318 | date = January 2018 | pmid = 29361745 | pmc = 5796261 | doi = 10.3390/ijms19010318 | doi-access = free }} Several recessive, inactivating mutations in TREM2 and TYROBP (encodes DAP12 protein) have been identified that can cause PLOSL.{{cite journal | vauthors = Paloneva J, Kestilä M, Wu J, Salminen A, Böhling T, Ruotsalainen V, Hakola P, Bakker AB, Phillips JH, Pekkarinen P, Lanier LL, Timonen T, Peltonen L | display-authors = 6 | title = Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts | journal = Nature Genetics | volume = 25 | issue = 3 | pages = 357–361 | date = July 2000 | pmid = 10888890 | doi = 10.1038/77153 | s2cid = 9243117 }}{{cite journal | vauthors = Walter J | title = The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases | journal = The Journal of Biological Chemistry | volume = 291 | issue = 9 | pages = 4334–4341 | date = February 2016 | pmid = 26694609 | pmc = 4813462 | doi = 10.1074/jbc.R115.704981 | doi-access = free }} The mutations prevent association between TREM2 and DAP12 or expression of shorter, non-functional forms of TREM2. Loss of function of TREM2 signaling increases the inflammatory responses of microglia, reducing clearance of dead neurons and promoting inflammation and even formation of amyloid plaques.

During ischemic stroke, microglia respond to the area of insult. TREM2 appears to reduce the inflammatory response induced by TLR signaling and promote microglial migration, survival, and regeneration.{{cite journal | vauthors = Gervois P, Lambrichts I | title = The Emerging Role of Triggering Receptor Expressed on Myeloid Cells 2 as a Target for Immunomodulation in Ischemic Stroke | journal = Frontiers in Immunology | volume = 10 | pages = 1668 | date = 2019 | pmid = 31379859 | pmc = 6650572 | doi = 10.3389/fimmu.2019.01668 | doi-access = free }}{{cite journal | vauthors = Ulrich JD, Holtzman DM | title = TREM2 Function in Alzheimer's Disease and Neurodegeneration | journal = ACS Chemical Neuroscience | volume = 7 | issue = 4 | pages = 420–427 | date = April 2016 | pmid = 26854967 | doi = 10.1021/acschemneuro.5b00313 }}

TREM2 has also been linked to additional disorders such as ALS, Parkinson's disease, and more dementia related conditions.

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.

In the brain, TREM2 is expressed on microglia that regulate clearance of neuronal debris. Binding of apolipoproteins, such as ApoE, to TREM2 promotes phagocytosis of apoptotic neurons or the uptake of amyloid beta by microglia.{{cite journal | vauthors = Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H, Li X, Rademakers R, Kang SS, Xu H, Younkin S, Das P, Fryer JD, Bu G | display-authors = 6 | title = Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) | journal = The Journal of Biological Chemistry | volume = 290 | issue = 43 | pages = 26043–26050 | date = October 2015 | pmid = 26374899 | pmc = 4646257 | doi = 10.1074/jbc.M115.679043 | doi-access = free }} Variants of TREM2 that encode proteins with reduced affinity for ligands have been associated with Alzheimer’s disease.{{cite journal | vauthors = Guerreiro R, Hardy J | title = TREM2 and neurodegenerative disease | journal = The New England Journal of Medicine | volume = 369 | issue = 16 | pages = 1569–1570 | date = October 2013 | pmid = 24143816 | doi = 10.1056/NEJMc1306509 | pmc = 3980568 }}

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.

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Category:Alzheimer's disease