Triggering receptor expressed on myeloid cells 2 also known as TREM-2 is a protein that in humans is encoded by the TREM2 gene. The TREM-2 protein is expressed primarily in immune cells across many different tissues. In the brain, this receptor is found in microglia [1], which are the central nervous system's immune response system [2]. In the liver, TREM2 is expressed in a multitude of cells, notably in macrophages that respond to insults to the tissue [3]. In the bowel and intestine, TREM2 is found on dendritic cells [4]. In these and other tissues, TREM2 is increasingly becoming an important receptor in different inflammatory diseases, and may have future potential as a therapeutic target.

Gene

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The TREM2 gene lies on the sixth chromosome in humans, specifically in location 6p21.1. The gene has 5 coding exon regions [5][6]. Alternative splicing of the TREM2 mRNA transcript leads to different isoforms of the protein being produced upon translation [5]. Specifically, TREM2 mRNA has 3 different isoforms containing three consistent exons, and two that vary between the isoforms [7]. Encoding for receptors in many different cell types, TREM2 mRNA is found in different organs across the body, but is most expressed in the brain, lungs, adrenal glands, placenta, gall bladder, and colon [5]. The TREM2 gene is present not only in humans, but in mice as well, which has allowed researchers to create a plethora of genetic models containing different mutations of the TREM2 gene to study the effects of these mutations in disease states [8]. In addition to the mouse, the TREM2 gene can be found in many animals along the evolutionary tree, including rats, dogs, monkeys and more [9].

In the brain, TREM2 is expressed differentially between brain regions, with the highest levels of this protein being found in the hippocampus, the white matter, and the spinal cord. In humans and mice, the levels of TREM2 increase with age [10].

Protein

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The TREM2 receptor with the ADAM10 and ADAM17 enzymes that create the soluble TREM2 fragment. Created with BioRender.com [11]

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 [12]. The extracellular component of TREM2 can bind different anionic ligands, specifically glycoproteins and lipids [13][14]. This ectodomain component includes an Ig-like V-type domain where ligands bind the receptor [15]. The TREM2 ectodomain is modified after the translation of the protein, which changes its affinity for binding to different ligands [7]. The intracellular component of TREM2 does not contain any signaling ability on its own, rather it works in tandem with the DNAX activator proteins 10 and 12 (DAP10, DAP12) to cause a downstream signal. A single TREM2 receptor may interact with both DAP10 and DAP12 at the same time [14].

Part of the ectodomain of TREM2 can be processed by enzymes a disintegrin and metalloprotease 10 and 17 (ADAM10, ADAM17) and released as a soluble version of the protein, referred to as soluble TREM2 (sTREM2) [7]. This protein fragment is released into the sera and CSF, and is currently being examined as a potential biomarker for disease in instances of neurodegeneration, but greater analysis is needed [7].

Function

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TREM2 structure as identified with X-ray crystallography. Image available through RCSB PDB. [16]

The TREM2 protein is found in immune cells termed myeloid cells, a category which include cells such as macrophages, granulocytes, monocytes, and dendritic cells [17]. In the brain, the receptor is only found in the microglial cells [10], which are analogous to the immune cells found peripherally. Monocyte/macrophage- and neutrophil-mediated inflammatory responses can be stimulated through G protein-linked 7-transmembrane receptors (e.g., FPR1), Fc receptors, CD14 and Toll-like receptors (e.g., TLR4), and cytokine receptors (e.g., IFNGR1) [18][19]. 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 [18][20].

In this myeloid immune response, upon stimulation by anionic molecules such as glycoproteins, DNA, bacterial fragments, or lipids [6][13][14][21], TREM2 engages DAP12, which is a homodimer, causing the two tyrosines on its immunoreceptor tyrosine-based activation motif (ITAM) to become phosphorylated by Src tyrosine kinases [14]. Spleen tyrosine kinase (Syk) interacts with these phosphorylation sites and activates the phosphatidylinositol-3 kinase (PI3K) cascade, in addition to other secondary signaling molecules including mTOR, MAPK, and ERK [14][22]. When TREM2 is associated with the DAP10 protein, the primary pathway activated is PI3K [23]. The PI3K pathway supports cellular functions through the expression of transcription factors AP1, NF-κB, and NFAT [22]. Another main activity of this PI3K pathway is to increase intracellular calcium content, and activates calcium dependent kinases [22][23]. Anti-inflammatory gene transcription, including GAL1, GAL3, IL1RN, and progranulin are affected by TREM2 activation, another pathway through which this receptor modulates the immune response [14].

In a healthy condition, the main function of TREM2 is to act in support of bones, microglia, and hair follicles [14]. One of the homeostatic mechanisms through which TREM2 acts is to support synaptic pruning [7], a major function of microglia [24]. In disease states, conflicting reports on the effect of TREM2 activation make it an interesting receptor to study. While it has been reported that activating TREM2 results in both the activation of anti-inflammatory signaling, and increased phagocytosis [14], some evidence suggests that TREM2 can promote pro-inflammatory phenotypes [4][7]. Other evidence shows that TREM2 activity is able to ameliorate the pro-inflammatory cytokine response through modulation of TLR activation [22].

If TREM2 is cleaved and sTREM2 produced, the stereotypical TREM2 signaling cascade will not occur, even if the Ig like domain is bound by a ligand. sTREM2 is still found to have some functionality, and when an insult occurs, it may help myeloid cells avoid apoptosis. This truncated version of the receptor may also increase pro-inflammatory phenotypes [14]. sTREM2 has been indicated in activating downstream pathways such as PI3K and ERK through an unidentified receptor [25].

Association with diseases

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Given the intrinsic roles that myeloid cells and the inflammatory system play in most diseases, receptors that activate these cells are likely to play a role in these diseases. Genetic and experimental evidence has shown that TREM2 is involved in many diseases, and in the case of Nasu-Hakola Disease, can play a causative role [26].

 
The major AD-associated TREM2 mutations lead to decreased binding affinity for AD ligands, and this leads to a reduced microglial response to AB plaques. Created with BioRender.com [27]

Alzheimer's Disease

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There are different genetic variants of TREM2 that are associated with multiple neurodegenerative disorders. Through genetic analysis, TREM2 mutations have been found to be a strong risk factor for Alzheimer's disease [28]. It is found that these mutations are just as related to the development of Alzheimer's as the well known ApoE4 mutation [21]. TREM2 is involved in the microglial response to the amyloid plaques that are characteristic of AD, and when the receptor is in some way disrupted, the microglial response to plaques is reduced, and the plaques appear to take on a more toxic state [28]. The exact role of TREM2 in AD pathology appears to vary depending on the stage of AD, with some evidence suggesting that as the disease reaches later stages,

When microglia surround amyloid plaques, the plaques are found to be denser. In animals that contains a mis-sense TREM2-R47H mutation that is related to AD or if the animal lacks the TREM2 receptor, it is seen that the plaques enter the more toxic state that negatively affects local neurons [28]. This mutation, as well as the TREM2-R62H mutation, decreases the affinity of the TREM2 receptor for AD ligands, including the AD associated lipoprotein APOE, although some recent evidence suggests that these mutations do not affect the binding of these ligands [12][29]. The TREM2 receptor is able to bind these lipoproteins that are associated with AD, and when this binding occurs the microglia are able to better phagocytose pieces of the plaques [28]. In studies of the AD-linked mutations and TREM2 impairment, we see that microglia are less responsive to the AB plaques that are the major pathology in the disease [29]. TREM2 may also influence AD through its ability to bind to AB42 and impede oligomerization [12], which has been indicated as a toxic and detrimental aspect of AD [30]. During and before AD, it has been found that sTREM2 levels are higher than in healthy controls, and may be a biomarker that is useful during the onset of AD for assessing damage. The soluble ectodomain may also be neuroprotective due to its ability to bind plaque pathology [7].

Cancer

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The immune system plays an intricate role in the development of cancers, and can either be beneficial for a patient, or assist in the growth of a tumor. It has been found that TREM2 is important in the role myeloid cells play in cancer development. TREM2 is found to have an increased expression in macrophages that are responding to tumors, in both humans and in rodent models [14]. TREM2 interacts with the tumor microenvironment in a multitude of ways, and has been found to be tumor suppressant through its down-regulation of the TLR4 pro-inflammatory signaling pathway [23]. TREM2 has been found to have differential expression from healthy conditions in specific cancers, including lung cancer, gastric cancer, and perhaps gliomas and liver cancer as well [14].

In contrast to the evidence supporting TREM2's role as a tumor suppressant, it has also been found that increased activation and expression of TREM2 has deleterious effects on the disease [14]. Specifically in gastric cancer, a greater expression of TREM2 is found to be correlated with a worse disease outcome, and in a model of esophageal adenocarcinoma, a reduction in TREM2 led to a more positive outcome [23].

Inflammatory bowel disease

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In inflammatory bowel disease (IBD), TREM2 expressed in human monocyte dendritic cells (DC) [4], the antigen presenting cells that are involved in the immune response in the intestine and bowel, appears to play a role in the disease [31]. For IBD, the expression of TREM2 is limited to inflamed sections of the bowel and has a pro-inflammatory effect as opposed to its role in other disease states [4]. TREM2 produces this inflammatory effect through increasing the release of pro-inflammatory cytokines, and may be involved in changes to the gut microbiome through DC mediated deaths of bacteria [4].

Liver disease

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TREM-2 is expressed in a variety of liver cells, and is seen to play a role in multiple different inflammatory liver diseases [32]. It appears as though the expression of TREM-2 in hepatic cells is related to a reduction in inflammation, with an increase in TREM2 expression in hepatic stellate cells being related to decreased inflammatory response [3]. TREM2 is also expressed in Kupffer cells, which are macrophages that are specific to the liver [32].

In liver diseases, it has been proposed that TREM2 expressing macrophages are able to interact with specific liver endothelial cells that had a certain expression profile. In this capacity, TREM2 may be allowing cell-to-cell communication that allows for liver recovery in the disease state [32]. The TREM2/DAP12 complex leads to a decrease in inflammation in liver disease by inhibiting down-stream signaling molecules that activate pro-inflammatory cytokines and by inhibiting TLR4 signaling [3]. In fatty liver disorders, the increase in lipids leads to a down-regulation of TREM2. This can be problematic in disease as proper functioning of TREM2 leads to lipid phagocytosis and a decrease in damage-causing entities, such as reactive oxygen species [3].

 
Mutations in either TREM2 or DAP12 are causative in the development of Nasu-Hakola Disease. This disease is characterized by dysfunctional microglia, bone cysts and fractures, frontal lobe syndrome, and dementia. Created with BioRender.com [33]

Nasu-Hakola Disease

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Nasu-Hakola Disease (NHD), a neurodegenerative disorder that is classified by bone cysts, dementia, and accelerated death, also has a genetic risk linked to the TREM2 gene [26]. In the stereotypical bone cysts that form in NHD, it is found that there is fat in lieu of bone marrow [22]. In this disease, the main cell type in the brain that is affected is the microglia, where TREM2 is expressed [34]. Not just correlative, there are multiple TREM2 mutations found to be causative in the development of many cases of NHD, as well as mutations in the TYROBP gene (encodes DAP12 protein) that can cause other cases of the disease [15][35]. The mutations associated with NHD are recessive genes, so both alleles need to have the mutation for disease phenotype to occur [36]. In many patients, this down-regulation of TREM2 can lead to an acceleration in disease progression, due to an increase in the inflammatory response of microglia [34].

The mutations of TREM2 found in NHD generally lead to a receptor that cannot associate with the DAP12 signaling protein, the absence of the receptor, or the receptor is found to be a shorter, non-functional protein [22][36]. NHD microglia with mutated TREM2 or TYROBP are found to have reduced functionality in clearing dead neurons, induce a more pro-inflammatory phenotype, and even influences the formation of amyloid plaques [34].

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It has been shown that TREM2 is necessary for the formation of macrophages in adipose tissue, and that metabolism can become dysfunctional in the absence of the receptor. Lipid associated macrophages that are positive for TREM2 are found in obese adipose tissue, and when a mouse has a TREM2 knockdown, these macrophages are not formed, and the absence of these macrophages is linked to dysfunctional metabolism [14].

Stroke

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Ischemic stroke, a leading cause of disability, has many pathways through which damage occurs. TREM2 has been identified as a potential modulator for this cerebrovascular disorder. Microglia respond to the area of insult, and TREM2 appears to reduce the inflammatory phenotype caused by Toll-like receptors and converts microglia to working on recovery following the event [37]. TREM2 knockout mice are found to have low microglial response to a stroke, and had worse recovery from the stroke. This further suggest that TREM2 helps activate a restorative microglial response to damage [38]. In the event of a stroke, a study has found that the expression of TREM2 on microglia influences the recovery of the stroke, however the TREM2 on macrophages is unrelated to the response [37].

Other diseases

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TREM2 has also been linked to additional disorders such as ALS, Parkinson's disease, and more dementia related conditions [15].

Therapeutic potential

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Given the role that TREM2 plays in these many diseases, it is an interesting potential target for therapeutics. In order to affect TREM2, different techniques are being considered, including small molecules and antibody therapeutics [12]. Given the lack of specific binding molecules, the direct targeting of TREM2 is a challenge that must be overcome [12]. 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 treated rodents had lower plaques than the controls [14].

Currently, in humans, a phase II clinical trial of a compound called AL002 is ongoing, testing a treatment that is targeting TREM2 for efficacy [39]. Alector Inc. is testing a monoclonal antibody treatment that is being considered as a potential treatment for patients in earlier stages of Alzheimer's disease, with the goal of increasing TREM2 activity, and thus the brains immune response to the disease [40].

Another clinical trial is in phase I for tolerability is assessing a therapeutic called PY314 for gastric cancer [41]. The intended mechanism of this therapeutic is to reduce TREM2 expressing cells in the tumor microenvironment, and this would lead to an increase in an immune response to the tumor [41].

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