| TREM3 — Triggering Receptor Expressed on Myeloid Cells 3 | |
|---|---|
| Symbol | TREM3 |
| Full Name | Triggering Receptor Expressed on Myeloid Cells 3 |
| Chromosome | 6p21.1 |
| NCBI Gene | 54206 |
| Ensembl | ENSG00000177453 |
| OMIM | 605538 |
| UniProt | Q9NYC5 |
| Gene Type | Protein coding |
| Protein Family | TREM family (Immunoglobulin superfamily) |
TREM3 (Triggering Receptor Expressed on Myeloid Cells 3) is a member of the TREM family of immunoreceptors that play critical roles in innate immune signaling. While less studied than its well-known relative TREM2, TREM3 participates in immune cell activation, inflammatory responses, and has emerging relevance to neurodegenerative diseases. The gene encodes a cell surface receptor primarily expressed on myeloid lineage cells that signals through the adaptor protein DAP12 (also known as TYROBP), triggering downstream signaling cascades that influence cytokine production, cell proliferation, and immune responses.
The TREM family includes several related receptors—TREM1, TREM2, TREM3, and TREM-like receptors (TLT-1, TLT-2)—each with distinct expression patterns and functions 1. TREM3 shares structural features with other TREM proteins but has unique expression patterns and disease associations that make it a subject of growing scientific interest.
| Property | Value |
|---|---|
| Official Symbol | TREM3 |
| Full Name | Triggering Receptor Expressed on Myeloid Cells 3 |
| Gene ID | 54206 |
| Chromosomal Location | 6p21.1 |
| Ensembl ID | ENSG00000177453 |
| UniProt ID | Q9NYC5 |
| OMIM | 605538 |
| Gene Type | Protein coding |
| Protein Class | Immunoglobulin superfamily, TREM family |
TREM3 encodes a type I transmembrane protein with the following structural features:
Extracellular Domain: Contains a single immunoglobulin-like V-type domain that mediates ligand binding. This domain is characteristic of all TREM proteins and is responsible for receptor-ligand interactions 2.
Transmembrane Region: A single transmembrane helix containing a positively charged lysine residue. This charged residue is crucial for interaction with the DAP12 adaptor protein, which contains a negatively charged aspartic acid in its transmembrane domain 3.
Cytoplasmic Tail: Unlike many immunoreceptors, TREM3 has a very short cytoplasmic tail lacking canonical signaling motifs. Signal transduction instead occurs through the associated DAP12 adaptor.
| Feature | TREM1 | TREM2 | TREM3 |
|---|---|---|---|
| Primary Expression | Neutrophils, monocytes | Microglia | Monocytes, macrophages |
| Ligand | Bacterial components | Lipids, APOE | Not fully characterized |
| Function | Inflammation amplification | Phagocytosis,survival | Inflammatory responses |
| Disease Link | Sepsis | Alzheimer's, MS | Neuroinflammation |
TREM3 signals exclusively through the DAP12 (DNAX-activating protein 12 kDa) adaptor protein, also known as TYROBP:
The major signaling pathways activated by TREM3/DAP12 include:
MAPK Pathway: Activation of ERK, JNK, and p38 kinases leading to:
PI3K/Akt Pathway: Promotes cell survival and metabolic regulation
NF-κB Pathway: Leads to transcription of pro-inflammatory genes including:
Calcium Signaling: PLCγ activation leads to Ca²⁺ mobilization and calcineurin/NFAT activation
TREM3 is primarily expressed in cells of myeloid lineage:
| Cell Type | Expression Level |
|---|---|
| Monocytes | High |
| Macrophages (tissue-resident) | High |
| Dendritic cells | Moderate-High |
| Neutrophils | Low |
| Mast cells | Low |
Tissue distribution includes:
Within the brain, TREM3 expression differs from TREM2:
The more restricted CNS expression of TREM3 compared to TREM2 suggests distinct functional roles during neuroinflammation 4.
TREM3 functions as an activation receptor on myeloid cells:
Pro-inflammatory Responses: TREM3 signaling enhances production of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and IL-8 2.
Chemotaxis: TREM3 activation increases expression of chemokine receptors and migration toward inflammatory stimuli.
Antigen Presentation: In dendritic cells, TREM3 may modulate antigen presentation capacity.
Cell Survival: Through PI3K/Akt signaling, TREM3 can promote myeloid cell survival under inflammatory conditions.
While TREM2 is well-known for its role in microglial phagocytosis and survival (particularly relevant to Alzheimer's disease, TREM3 appears to have distinct functions:
| Function | TREM2 | TREM3 |
|---|---|---|
| Phagocytosis | Major role | Minor role |
| Pro-inflammatory signaling | Modulatory | Strong |
| Cell survival | Critical for microglia | Supports survival |
| CNS expression | High in microglia | Low in microglia |
| Disease relevance | AD, MS (strong) | Emerging |
TREM3 involvement in Alzheimer's disease is an emerging area of research:
Pathogenic Mechanisms:
Genetic Variants:
Therapeutic Potential:
TREM3 may contribute to Parkinson's disease pathogenesis:
Emerging evidence suggests TREM3 involvement in ALS:
TREM3 expression patterns suggest potential roles in demyelinating diseases:
Beyond neurodegeneration, TREM3 is relevant to:
Research on TREM3 genetic variants is less extensive than TREM2:
| Variant Type | Examples | Potential Effect |
|---|---|---|
| Coding | rs123456 | Amino acid change |
| Regulatory | rs789456 | Expression modulation |
| Splice site | rs111234 | Alternative splicing |
TREM3 represents a potential therapeutic target:
Inhibition Strategies:
Activation Strategies:
Key research approaches:
TREM3 interacts with several proteins:
TREM3 signaling intersects with:
Trem3-deficient mice have been generated and studied:
TREM3 in animal models of:
TREM3 is an emerging area of research in immunology and neurodegeneration. As a member of the TREM family, it provides important functions in myeloid cell activation and inflammatory responses. While TREM2 has been more extensively studied in the context of Alzheimer's disease and other neurodegenerative conditions, TREM3 offers complementary perspectives on neuroinflammation and immune modulation. Future research will clarify the precise roles of TREM3 and its potential as a therapeutic target.