TREM2

Key takeaways

TREM2 belongs to biology; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect TREM2 to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of TREM2 from memory before moving on to harder problems.

Reference excerpt

Triggering receptor expressed on myeloid cells 2 (TREM2) 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 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. 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, Trem2. 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

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. 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. 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 (TAMs) have been characterized by expression of TREM2. 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. Conversely, TREM2 expression is reduced following inflammatory signaling induction by lipopolysaccharide (a TLR4 ligand) or interferon gamma (IFNG). 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.

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).

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with TREM2

Start with the simplest possible case. Write down what TREM2 claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to TREM2 before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about TREM2 ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of TREM2

In research: TREM2 appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses TREM2 in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: TREM2 is common in secondary-school and first-year university syllabi. It links to neighbouring topics Alzheimer's disease, Genes on human chromosome 6, so understanding it makes those chapters shorter.
In everyday life: Look for TREM2 outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study TREM2 in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what TREM2 means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain TREM2 out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is TREM2 in simple terms?

Triggering receptor expressed on myeloid cells 2 (TREM2) 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.

Why does TREM2 matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study TREM2?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on TREM2.