TREM2
Triggering receptor expressed on myeloid cells 2 '' is a protein that in humans is encoded by the TREM2 gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cells in the central nervous system. In the liver, TREM2 is expressed by several cell types, including macrophages, that respond to injury. In the intestine, TREM2 is expressed by myeloid-derived dendritic cells and macrophage. TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target.
Gene
The ' 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. Specifically, TREM2 mRNA has 3 different isoforms containing 3 consistent exons, and 2 that vary between the isoforms. 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, '. 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, 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. 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 and released as a soluble version, called soluble TREM2. This protein fragment is released into the serum and cerebral spinal fluid, and might serve as a biomarker for neurodegenerative and other disorders, but further studies are needed.
Function
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, Fc receptors, CD14, toll like receptors, and cytokine receptors. 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 of DAP12 by SRC tyrosine kinases. Spleen tyrosine kinase interacts with these phosphorylation sites and activates the phosphatidylinositol-3 kinase signaling pathway, as well as other signaling molecules such as mTOR, MAPK, and ERK. Association of TREM2 with DAP10 also activates the PI3K signaling pathway, 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 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. 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 have been characterized by expression of TREM2. TREM2 signaling leads to downregulated transcription of genes that promote inflammation, 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. 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 or interferon gamma. 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. sTREM might therefore have pro-inflammatory effects. sTREM2 has been indicated in activating signaling pathways such as PI3K and ERK through an unidentified receptor. 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.