Triggering Receptor Expressed on Myeloid Cells 3 (TREM3)

Triggering Receptor Expressed on Myeloid Cells 3 (TREM3)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TREM3 — Triggering Receptor Expressed on Myeloid Cells 3</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>TREM3</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Triggering Receptor Expressed on Myeloid Cells 3</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>6p21.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/54206" target="_blank">54206</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000177453" target="_blank">ENSG00000177453</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/605538" target="_blank">605538</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9NYC5" target="_blank">Q9NYC5</a></td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein coding</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>TREM family (Immunoglobulin superfamily)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

TREM3 — Triggering Receptor Expressed on Myeloid Cells 3

Overview

Triggering Receptor Expressed on Myeloid Cells 3 (TREM3)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TREM3 — Triggering Receptor Expressed on Myeloid Cells 3</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>TREM3</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Triggering Receptor Expressed on Myeloid Cells 3</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>6p21.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/54206" target="_blank">54206</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000177453" target="_blank">ENSG00000177453</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/605538" target="_blank">605538</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9NYC5" target="_blank">Q9NYC5</a></td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein coding</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>TREM family (Immunoglobulin superfamily)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

TREM3 — Triggering Receptor Expressed on Myeloid Cells 3

Overview

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.[@chen2020] While less studied than its well-known relative [TREM2](/proteins/trem2), TREM3 participates in immune cell activation, inflammatory responses, and has emerging relevance to neurodegenerative diseases.[@hu2019] 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 downst[@wu2017]ream 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](https://pubmed.ncbi.nlm.nih.gov/10561575/). 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.

Gene Overview

| 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 |

Molecular Structure

Protein Architecture

TREM3 encodes a type I transmembrane protein with the following structural features:

Comparison with Other TREM Proteins

| 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 |

Signaling Mechanisms

DAP12-Dependent Signaling

TREM3 signals exclusively through the DAP12 (DNAX-activating protein 12 kDa) adaptor protein, also known as TYROBP:

Downstream Pathways

The major signaling pathways activated by TREM3/DAP12 include:

• Cell proliferation and differentiation
• Cytokine production
• Stress responses

• IL-1β, IL-6, TNF-α
• Chemokines (CCL2, CXCL8)
• Adhesion molecules

Expression Pattern

Peripheral Expression

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:

• Blood: Monocytes are the primary circulating TREM3-expressing cells
• Spleen: High expression in splenic macrophages
• Lung: Alveolar macrophages express TREM3
• Liver: Kupffer cells (liver macrophages) express TREM3
• Gut: Intestinal macrophages show TREM3 expression

Central Nervous System Expression

Within the brain, TREM3 expression differs from TREM2:

• Microglia: Low baseline expression in resident microglia
• Infiltrating Macrophages: Higher expression in monocyte-derived macrophages that infiltrate the CNS during inflammation
• Induction: TREM3 expression increases under inflammatory conditions

Biological Functions

Immune Cell Activation

TREM3 functions as an activation receptor on myeloid cells:

Comparison with TREM2

While TREM2 is well-known for its role in microglial phagocytosis and survival (particularly relevant to [Alzheimer's disease](/diseases/alzheimers-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 |

Disease Associations

Alzheimer's Disease

TREM3 involvement in Alzheimer's disease is an emerging area of research:

Pathogenic Mechanisms:

• Microglial Activation: TREM3 may contribute to chronic microglial activation in AD brain [5](https://pubmed.ncbi.nlm.nih.gov/27021476/)
• Cytokine Production: TREM3-driven inflammation could exacerbate neuroinflammation
• Interaction with TREM2: TREM3 may modulate or compete with TREM2 signaling

• Limited data on TREM3 genetic variants in AD
• The TREM gene cluster on chromosome 6p21.1 is of interest for immune-related diseases

• TREM3 modulation as a strategy to modulate neuroinflammation
• Challenges include understanding precise TREM3 functions in brain

Parkinson's Disease

TREM3 may contribute to Parkinson's disease pathogenesis:

Amyotrophic Lateral Sclerosis (ALS)

Emerging evidence suggests TREM3 involvement in ALS:

• Motor Neuron Environment: TREM3-expressing immune cells in the spinal cord
• Inflammatory Contribution: Potential role in the chronic inflammation observed in ALS
• Disease Progression: Correlation with inflammatory markers in some studies

Multiple Sclerosis

TREM3 expression patterns suggest potential roles in demyelinating diseases:

• Lesion Environment: TREM3+ cells in MS demyelinating lesions
• Demyelination: Contribution to inflammatory processes affecting myelin
• Remyelination: Potential effects on oligodendrocyte progenitor cells

Inflammatory Diseases

Beyond neurodegeneration, TREM3 is relevant to:

Genetic Variants

Known Polymorphisms

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 |

Clinical Significance

• Limited evidence for TREM3 variants as disease risk factors
• Some variants may affect immune response magnitude
• Further research needed on functional variants

Therapeutic Implications

Therapeutic Targeting

TREM3 represents a potential therapeutic target:

• Blocking antibodies against TREM3
• Soluble TREM3 ectodomain as decoy
• Small molecule inhibitors of TREM3/DAP12 interaction

• Agonistic antibodies for certain indications
• Enhanced immune responses against infections

Clinical Development Status

• Preclinical stage for most TREM3-targeted approaches
• Lessons from TREM2 drug development inform TREM3 strategies
• Challenges include:
• Limited understanding of TREM3 ligands
• Complexity of immune modulation
• Potential for unintended immune suppression

Research Methods

Studying TREM3

Key research approaches:

Model Systems

• Cell Lines: THP-1 (monocytic), RAW264.7 (macrophage)
• Mouse Models: Trem3 knockout mice available
• Primary Cells: Human monocytes, monocyte-derived macrophages

Interactions and Pathways

Protein-Protein Interactions

TREM3 interacts with several proteins:

Pathway Integration

TREM3 signaling intersects with:

• TLR Signaling: Can synergize with Toll-like receptor responses
• Cytokine Networks: Influences IL-1, IL-6, TNF pathways
• Phagocytosis Machinery: Modulates uptake functions

Animal Models

Knockout Mice

Trem3-deficient mice have been generated and studied:

• Viable and Fertile: Baseline phenotype relatively normal
• Immune Alterations: Changes in macrophage responses
• Disease Models: Used to assess TREM3 in various conditions

Disease Models

TREM3 in animal models of:

• Alzheimer's Disease: APP/PS1 mice crossed with Trem3-/-
• Parkinson's Disease: MPTP models
• Multiple Sclerosis: EAE model

Future Directions

Unanswered Questions

Emerging Research Areas

See Also

• [TREM2](/proteins/trem2) — Related TREM family protein in neurodegeneration
• [Microglia](/cell-types/microglia-neuroinflammation) — TREM3-expressing cells in the brain
• [Neuroinflammation](/mechanisms/neuroinflammation-pathway) — Core mechanism
• [Alzheimer's Disease](/diseases/alzheimers-disease/) — Primary disease association
• [Parkinson's Disease](/diseases/parkinsons-disease/) — Secondary disease association
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) — Disease association
• [Genes Directory](/genes/)

External Links

• [NCBI Gene: TREM3](https://www.ncbi.nlm.nih.gov/gene/54206)
• [UniProt: Q9NYC5](https://www.uniprot.org/uniprot/Q9NYC5)
• [Ensembl: ENSG00000177453](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000177453)
• [OMIM: 605538](https://omim.org/entry/605538)

Summary

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.

Additional Resources

• [TREM Family Overview](/proteins/trem-family-overview)
• [Neuroinflammation Mechanisms](/mechanisms/neuroinflammation-pathway)
• [DAP12 Signaling in Immune Cells](https://pubmed.ncbi.nlm.nih.gov/14528288/)

References

Clinical Perspectives

Diagnostic Applications

TREM3 biomarkers and diagnostics:

Genetic Markers:

• TREM3 variants and disease risk
• Haplotype analysis
• Population genetics

• Soluble TREM3 in circulation
• CSF TREM3 levels
• Correlations with disease activity

• TREM3+ monocyte frequency
• Activation status assessment
• Flow cytometry detection

Therapeutic Development

TREM3-targeted interventions:

Inhibition Strategies:

• Monoclonal antibodies against TREM3
• Soluble receptor decoys
• Small molecule antagonists

• Agonistic antibodies
• Gene therapy approaches
• Enhanced immune responses

Clinical Development Status

Current state of TREM3 therapeutics:

Safety Considerations

For TREM3-targeted therapy:

Clinical Applications

Potential therapeutic uses:

• Inflammatory Diseases: Autoimmune conditions
• Infectious Disease: Enhanced immunity
• Cancer Immunotherapy: Immune activation
• Transplantation: Immune modulation

Combination Therapy

TREM3-based combination approaches:

Regulatory Considerations

For TREM3 clinical development:

Economic Analysis

TREM3 therapy development:

• Drug discovery costs
• Clinical trial investments
• Manufacturing expenses
• Market potential

Global Health Impact

TREM3-targeted interventions:

• Infectious disease treatment
• Autoimmune disease management
• Cancer immunotherapy
• Inflammatory conditions

Research Infrastructure

Required resources:

• Antibody development facilities
• Mouse model systems
• Patient sample collections
• Clinical trial networks

Training Needs

Expertise required:

Funding Landscape

Support for TREM3 research:

• Pharmaceutical industry investment
• NIH grant funding
• Foundation support
• Academic partnerships

Competitive Landscape

TREM3 versus other immune targets:

| Target | Function | Development Stage | Market Potential |
|--------|----------|-------------------|------------------|
| TREM3 | Immune activation | Preclinical | Moderate |
| TREM2 | Phagocytosis | Clinical | High |
| TREM1 | Inflammation | Clinical | Moderate |
| SIRPα | Immune checkpoint | Clinical | High |

Future Directions

Emerging research areas:

Conclusion

TREM3 represents an emerging immunotherapeutic target with potential applications in infectious disease, autoimmunity, and cancer. While significantly less studied than TREM2, TREM3 offers unique perspectives on myeloid cell activation and inflammatory responses. Continued research will clarify its precise roles and enable development of TREM3-targeted interventions.