TREM1 Human

What is TREM1 and what cellular populations express it?

TREM1 is a pattern recognition receptor and member of the Ig-like immunoregulatory receptor family that functions as a major amplifier of innate immune responses . It is predominantly expressed on myeloid cells, with highest expression observed on neutrophils and monocytes . TREM1 is constitutively expressed on the surfaces of unstimulated human neutrophils and has also been documented on macrophages in certain tissue environments, particularly in inflammatory and tumor contexts .

Research demonstrates that TREM1 expression increases following acute and chronic injury in various tissues , indicating dynamic regulation in tissue-specific contexts. The expression pattern can vary significantly based on the inflammatory environment and disease context, making it an important consideration for experimental design when studying this receptor.

What is the difference between membrane-bound TREM1 and soluble TREM1?

Membrane-bound TREM1 contains both an extracellular domain and a transmembrane region, allowing it to transmit signals upon ligand binding . In contrast, soluble TREM1 (sTREM1) is generated through alternative splicing of TREM1 mRNA, resulting in a 30-kDa protein that lacks the transmembrane region . This soluble form contains the same extracellular domain as membrane-bound TREM1 but is secreted rather than attached to the cell membrane.

The functional difference is significant: while membrane-bound TREM1 can bind ligands and initiate signaling cascades that amplify inflammatory responses, sTREM1 can bind the same ligands but cannot transmit signals, potentially serving as a decoy receptor that downregulates TREM1 signaling pathways . This suggests sTREM1 might function as an endogenous negative regulator of TREM1-mediated inflammation. Importantly, sTREM1 has been detected in plasma from volunteers injected with LPS and from patients with sepsis, and has been proposed as a diagnostic marker for infection in patients with pneumonia and as a prognostic marker for patients with septic shock .

How does TREM1 contribute to innate immune responses?

TREM1 functions as a potent amplifier of pro-inflammatory innate immune responses by synergizing with both Toll-like receptors (TLRs) and pattern recognition receptors of the NACHT-LRR class . Upon activation, TREM1 promotes the amplification of inflammatory signals that are initially triggered by TLRs , leading to enhanced production of cytokines, reactive oxygen species, and increased intracellular calcium release .

This amplification effect is critical in both acute and chronic inflammatory conditions. In acute settings such as sepsis, TREM1 activation contributes to robust neutrophil and monocyte responses necessary for pathogen clearance . In chronic inflammatory contexts such as atherosclerosis, TREM1 signaling exacerbates monocytosis by influencing myeloid differentiation toward increased monocyte output . Additionally, TREM1 impacts lipid metabolism in myeloid cells, augmenting pro-inflammatory cytokine responses and foam cell formation in human monocytes/macrophages .

The significance of TREM1 in innate immunity is further highlighted by studies showing that pharmacological inhibition of TREM1 confers protection in preclinical models of both infectious and non-infectious inflammatory disorders .

What are the mechanisms of TREM1 activation?

TREM1 is activated through multimerization on the cell surface, with the degree of clustering directly correlating with the intensity of downstream signaling events . This activation process differs between neutrophils and monocytes. In monocytes, TREM1 activation by LPS requires a two-step process: first, upregulation of TREM1 expression, followed by clustering of TREM1 at the cell surface . In contrast, neutrophils exhibit a rapid cell membrane reorganization of TREM1 in response to LPS .

The adapter protein DAP12 plays a crucial role in TREM1 activation by stabilizing its surface expression and facilitating multimerization . Following receptor clustering, the associated DAP12 becomes phosphorylated at its immunoreceptor tyrosine-based activation motif (ITAM), initiating downstream signaling cascades.

What is the role of TREM1 in cancer?

TREM1 plays a significant role in cancer development and progression through multiple mechanisms. In colorectal cancer, genetic deficiency of TREM1 (Trem1⁻/⁻) protects against tumorigenesis in models of inflammation-driven cancer . Compared to adjacent tumor-free colonic mucosa, expression of TREM1 is increased in both murine and human colorectal tumors .

Gene expression analysis reveals distinct immune signatures between Trem1⁻/⁻ and Trem1⁺/⁺ tumors. While Trem1⁻/⁻ tumors show increased abundance of transcripts linked to adaptive immunity, Trem1⁺/⁺ tumors are characterized by overexpression of innate pro-inflammatory genes associated with tumorigenesis .

TREM1 is highly expressed by tumor-infiltrating neutrophils, which represent the predominant myeloid population in Trem1⁺/⁺ tumors but not in Trem1⁻/⁻ tumors . This suggests that TREM1-expressing neutrophils are critical players in colorectal tumor development.

Pan-cancer analyses have further demonstrated that TREM1 expression is elevated in most cancer types . High TREM1 expression correlates with unfavorable prognosis and is associated with an immune-suppressive tumor microenvironment characterized by increased myeloid cell infiltration and decreased CD8+ T cell activity . These findings highlight TREM1's potential as both a prognostic biomarker and therapeutic target in various cancer types.

What methodologies are most effective for studying TREM1 activation in primary human cells?

Studying TREM1 activation in primary human cells requires specialized approaches that account for the receptor's unique activation mechanisms and cell type-specific expression patterns. Based on the research literature, several methodological approaches have proven effective:

For investigating TREM1 multimerization-dependent activation:

• Crosslinking experiments using anti-TREM1 antibodies at various concentrations to induce different degrees of receptor aggregation, followed by measurement of downstream signaling events

• Proximity ligation assays to visualize and quantify TREM1 clustering on the cell surface in response to stimuli

• Co-immunoprecipitation studies to assess TREM1 interaction with DAP12 and formation of signaling complexes

For studying cell type-specific TREM1 regulation:

• Flow cytometry with careful isolation protocols that minimize artificial activation of neutrophils, avoiding techniques such as dextran sedimentation that may alter baseline expression

• In situ hybridization to detect Trem1 mRNA expressing cells in tissue contexts, distinguishing native expression from infiltrating cells

• Comparison of multiple neutrophil isolation techniques, as the method used can significantly impact TREM1 expression levels

For analyzing TREM1 function in disease models:

• TREM1 inhibition approaches using blocking antibodies, peptide inhibitors (LP17, LR12), or TREM-1 fusion proteins

• Genetic approaches using TREM1 knockout models or siRNA to assess receptor-specific effects

• Ex vivo stimulation of primary human monocytes with disease-relevant stimuli while manipulating TREM1 signaling

When working with primary human neutrophils, rapid isolation and experimental procedures are critical due to their short half-life and propensity for spontaneous activation.

How do researchers address conflicting data regarding TREM1 expression on neutrophils following LPS stimulation?

The literature presents contradictory findings regarding TREM1 surface expression on neutrophils after LPS stimulation, with some studies reporting upregulation and others reporting downregulation . Researchers have developed several approaches to address these discrepancies:

Methodological standardization:

• Critical evaluation of neutrophil isolation techniques, as different methods can yield different baseline TREM1 expression levels

• Standardizing the timing of measurements, as TREM1 expression may change dynamically over the course of stimulation

• Employing multiple complementary techniques to measure TREM1 expression, including flow cytometry, immunoblotting, and quantitative PCR

Experimental design considerations:

• Comparing in vitro versus in vivo LPS stimulation effects, as these may yield different results due to the complex in vivo environment

• Using dose-response curves rather than single concentrations of LPS to capture threshold effects

• Including time-course analyses to distinguish between early and late effects

Biological explanations for discrepancies:

• Investigating the role of neutrophil sequestration in apparent downregulation of TREM1 in in vivo models, as suggested by Knapp and colleagues

• Examining the concurrent production of soluble TREM1, which may influence detection of membrane-bound TREM1

• Assessing the impact of neutrophil activation state and priming on TREM1 expression

Advanced analytical approaches:

• Single-cell analysis to identify potential neutrophil subpopulations with differential TREM1 regulation

• Simultaneous assessment of multiple neutrophil activation markers alongside TREM1 to contextualize expression changes

What approaches are used to investigate TREM1's role in tumor microenvironments?

Investigating TREM1's role in tumor microenvironments requires specialized approaches that account for the complex cellular interactions and tissue contexts:

Tumor tissue analysis:

• Comparative gene expression analysis of tumor tissue from TREM1-deficient versus wild-type animals to identify distinct immune signatures

• In situ hybridization to detect Trem1 mRNA expressing cells within the tumor microenvironment

• Multi-parameter flow cytometry to identify and quantify TREM1-expressing cell populations in dissociated tumor tissue

Functional analysis:

• Experimental models of inflammation-driven tumorigenesis in TREM1-deficient versus wild-type animals to assess tumor development and progression

• Co-culture systems with tumor cells and TREM1-expressing myeloid cells to study cellular interactions

• Assessment of tumor infiltrating neutrophils and macrophages in relation to TREM1 expression

• Analysis of innate versus adaptive immune signatures in tumors with varying TREM1 expression levels

Clinical correlations:

• Evaluation of TREM1 expression in human tumor samples compared to adjacent normal tissue

• Correlation of TREM1 expression with clinical outcomes and patient survival

• Assessment of TREM1 as a potential biomarker for cancer prognosis or immunotherapy response

Bioinformatic approaches:

• Pan-cancer analysis of TREM1 expression across multiple cancer types using public databases

• Correlation of TREM1 expression with immune cell infiltration determined using multiple algorithms

• Functional enrichment analysis to decipher biological processes differentially regulated in high versus low TREM1-expressing tumors

How can researchers effectively inhibit TREM1 signaling in experimental settings?

Researchers have developed several approaches to effectively inhibit TREM1 signaling, each with distinct advantages for specific research questions:

Peptide-based inhibitors:

• LP17 and LR12 peptides, derived from the extracellular domain of TREM1, have been widely used to block TREM1 signaling in preclinical models

• These peptides compete with endogenous ligands for binding to TREM1, preventing receptor activation

• Dose optimization is critical as efficacy can vary across different experimental models

Protein-based approaches:

• TREM-1 fusion proteins, which incorporate the extracellular domain of TREM1 fused to an Fc fragment, act as decoy receptors to capture TREM1 ligands

• These fusion proteins often have longer half-lives than peptide inhibitors, allowing for less frequent dosing

Genetic approaches:

• TREM1 knockout (Trem1⁻/⁻) animal models provide complete absence of TREM1 signaling and have been instrumental in understanding its role in various disease contexts

• Conditional knockout models using Cre-lox systems allow for cell type-specific or inducible deletion of TREM1

• RNA interference (siRNA or shRNA) can be used for transient knockdown of TREM1 expression in specific tissues or cell populations

Antibody-based inhibition:

• Blocking antibodies directed against the ligand-binding domain of TREM1 can prevent receptor activation

• Monovalent antibody fragments (Fab) may be preferable to avoid potential receptor cross-linking that could activate rather than inhibit signaling

Complementary approaches:

• Inhibition of DAP12, the adapter protein essential for TREM1 signaling, can provide an alternative strategy to block TREM1 function

Each of these approaches has been successfully employed in research settings. Pharmacological inhibition of TREM1 has proven effective in preclinical mouse models of inflammatory disorders and malignancies, conferring survival advantages and protecting from organ damage or tumor growth by attenuating inflammatory responses .

How does TREM1 influence myelopoiesis in inflammatory conditions?

Research has revealed that TREM1 plays a significant role in regulating myelopoiesis, particularly in inflammatory conditions:

Mechanistic insights:

• TREM1 signaling exacerbates monocytosis in vivo by skewing myeloid differentiation toward increased monocyte output

• In atherosclerosis models, TREM1 influences the balance of myeloid cell populations, with TREM1-expressing neutrophils representing the predominant myeloid population in Trem1⁺/⁺ tumors but not in Trem1⁻/⁻ tumors

• TREM1 appears to impact the polarization of macrophages in tumor microenvironments, affecting the balance between pro-inflammatory and anti-inflammatory phenotypes

Experimental models demonstrating this effect:

• Atherosclerosis models using Apoe⁻/⁻ mice with or without TREM1 deficiency (Trem1⁻/⁻Apoe⁻/⁻ vs. Trem1⁺/⁺Apoe⁻/⁻) on high-fat, cholesterol-rich diets

• Bone marrow transplantation studies to distinguish intrinsic effects on hematopoietic cells from environmental factors

• Colorectal cancer models comparing tumor development in Trem1⁻/⁻ versus Trem1⁺/⁺ animals, with detailed analysis of myeloid cell infiltration

Analytical approaches:

• Flow cytometric analysis of bone marrow, blood, and tissue myeloid populations to track changes in cell populations and subsets

• Gene expression profiling of sorted myeloid populations to identify TREM1-dependent transcriptional programs

• Adoptive transfer experiments to track the fate of labeled myeloid cells in TREM1-sufficient versus TREM1-deficient environments

These findings demonstrate that TREM1 is not merely a receptor that amplifies inflammatory responses but also a regulator of myeloid cell development and differentiation, particularly under inflammatory conditions.

What methodologies are recommended for detecting and quantifying soluble TREM1 in clinical samples?

Detection and quantification of soluble TREM1 (sTREM1) in clinical samples require reliable and standardized methods:

Sample collection and processing:

• Standardized collection of plasma or serum with consistent use of anticoagulants when using plasma

• Prompt processing and storage at -80°C to prevent proteolytic degradation

• Collection at consistent time points when longitudinal monitoring is required, as sTREM1 levels may fluctuate during disease progression

Quantification methods:

• Enzyme-linked immunosorbent assay (ELISA) using antibodies specific for the extracellular domain of TREM1

• Multiplex bead-based assays for simultaneous measurement of sTREM1 alongside other inflammatory biomarkers

• Mass spectrometry-based approaches for absolute quantification and potential identification of sTREM1 isoforms

Quality control considerations:

• Inclusion of recombinant sTREM1 standards across a relevant concentration range

• Assessment of matrix effects that might interfere with detection in complex biological samples

• Validation of assay performance characteristics, including lower limit of detection, linearity, precision, and accuracy

Clinical implementation strategies:

• Establishment of reference ranges in healthy populations stratified by age, sex, and other relevant factors

• Consideration of comorbidities that might influence sTREM1 levels independently of the condition of interest

• Sequential measurements to evaluate trends rather than isolated values, particularly for monitoring disease progression or treatment response

It's important to note that sTREM1 has been detected in plasma from volunteers injected with LPS and from patients with sepsis . In sepsis patients, sTREM1 levels upon admission to intensive care were higher in survivors than in non-survivors, and a progressive decline in plasma sTREM1 concentration was associated with favorable clinical outcomes .

What are the experimental considerations when studying TREM1 in chronic versus acute inflammatory conditions?

Studying TREM1 in chronic versus acute inflammatory conditions requires distinct experimental approaches:

Temporal aspects:

• Acute models: Focus on early time points (hours to days) with frequent sampling to capture rapid changes in TREM1 expression and signaling

• Chronic models: Extended observation periods (weeks to months) with strategic sampling intervals to detect sustained alterations in TREM1 biology

• Consideration of both immediate and delayed effects of TREM1 inhibition, as outcomes may differ depending on when intervention occurs relative to disease onset

Model selection:

• Acute inflammation: Endotoxemia, sepsis models, or acute injury models (such as renal ischemia-reperfusion)

• Chronic inflammation: Atherosclerosis models, tumor development models, or chronic inflammatory bowel disease models

• Models that allow transition from acute to chronic phases to study TREM1's role in resolution versus persistence of inflammation

Cell population considerations:

• Acute settings: Focus on neutrophils, which are first responders and express high levels of TREM1

• Chronic settings: Greater emphasis on monocytes/macrophages and their differentiation states, as these cells play key roles in chronic inflammation

• Analysis of myeloid cell recruitment, retention, and turnover in affected tissues over time

Intervention strategies:

• Acute conditions: Immediate intervention with TREM1 inhibitors before or shortly after inflammatory trigger

• Chronic conditions: Both preventive (before disease onset) and therapeutic (after disease establishment) intervention protocols

• Consideration of intermittent versus continuous TREM1 inhibition in chronic models

Outcome measures:

• Acute models: Focus on rapid inflammatory mediators, neutrophil activation, and early tissue damage markers

• Chronic models: Assessment of tissue remodeling, fibrosis, cellular composition of affected tissues, and functional outcomes specific to the disease model

How do genetic variations in the TREM1 gene impact its function in human disease studies?

Genetic variations in the TREM1 gene can potentially impact its function and role in human diseases:

Types of genetic variations studied:

• Non-synonymous single nucleotide variants (SNVs) that alter the amino acid sequence of TREM1, such as the p.Thr25Ser variant

• Promoter variants that may affect TREM1 expression levels

• Splicing variants that could influence the ratio of membrane-bound to soluble TREM1

Methodological approaches:

• Genotyping large cohorts of patients with specific diseases and matched controls to identify disease associations

• Functional characterization of variants using cell-based assays to assess receptor expression, ligand binding, and signal transduction

• In silico prediction of variant effects on protein structure and function

Disease contexts where TREM1 variants have been studied:

• Kidney transplantation, where donor and recipient TREM1 gene variants have been analyzed for association with outcomes such as delayed graft function

• Sepsis and infectious diseases, where TREM1 plays a crucial role in amplifying inflammatory responses

• Chronic inflammatory conditions such as atherosclerosis

• Cancer, where variants might influence tumor-associated inflammation and disease progression

Results from human studies:

• In a kidney transplant cohort of 1263 matching donors and recipients, the TREM1 gene variant p.Thr25Ser was not associated with delayed graft function, biopsy-proven rejection, or death-censored graft failure

• Other studies have yielded variable results regarding associations between TREM1 variants and disease susceptibility or outcomes

Translational implications:

• TREM1 genetic profiling could potentially identify patient subgroups more likely to benefit from TREM1-targeted therapies

• Variants associated with altered TREM1 function might serve as natural models for understanding the consequences of therapeutic TREM1 modulation

What are the current challenges in developing TREM1-targeted therapies for inflammatory diseases?

Developing TREM1-targeted therapies for inflammatory diseases faces several significant challenges:

Target biology challenges:

• Incomplete understanding of natural TREM1 ligands and their tissue-specific expression patterns

• Complexity of TREM1 activation, which involves multimerization and interaction with DAP12

• Cell type-specific regulation of TREM1 expression and signaling between neutrophils and monocytes

• Potential redundancy in inflammatory amplification pathways that might compensate for TREM1 inhibition

Therapeutic development challenges:

• Designing inhibitors that effectively prevent TREM1 multimerization without triggering partial activation

• Balancing TREM1 inhibition to reduce pathological inflammation while preserving beneficial immune responses

• Determining optimal timing of TREM1-targeted interventions in acute versus chronic inflammatory conditions

• Developing delivery strategies that target specific tissue environments where TREM1 contributes to pathology

Clinical translation challenges:

• Identifying appropriate patient populations most likely to benefit from TREM1 inhibition

• Developing biomarkers (such as soluble TREM1) to monitor therapeutic efficacy

• Addressing potential disease-specific differences in TREM1 contribution to pathology

Recent research has shown variable effects of TREM1 inhibition across disease models. While pharmacological inhibition of TREM1 has proven effective in preclinical models of inflammatory disorders and malignancies , TREM1 interventions did not ameliorate ischemia-reperfusion-induced injury in renal models . These contrasting findings highlight the context-dependent role of TREM1 and underscore the importance of careful disease selection for clinical development.

How can TREM1 be targeted as a potential cancer therapeutic approach?

Research has identified several promising strategies for targeting TREM1 in cancer therapy:

Rationale for TREM1 targeting in cancer:

• TREM1 is elevated in most cancer types and verified in clinical samples

• Overexpression of TREM1 is linked with unfavorable prognosis in cancer patients

• TREM1 is positively correlated with immune-suppressive myeloid cell infiltration and negatively correlated with CD8+ T cell activity in tumors

• Tumors with high TREM1 levels are more resistant to immunotherapy

Therapeutic approaches:

• Direct TREM1 inhibition using peptide inhibitors (LP17, LR12) or fusion proteins that have shown efficacy in preclinical cancer models

• Combinatorial approaches targeting TREM1 alongside immune checkpoint inhibitors to enhance immunotherapy response in TREM1-high tumors

• Targeting myeloid cells in the tumor microenvironment to reduce TREM1-mediated immune suppression

• Repurposing existing drugs identified through connective map analysis, such as tozasertib and TPCA-1, which may counteract TREM1-associated gene signatures

Biomarker strategies:

• Using TREM1 expression levels for patient stratification in clinical trials

• Monitoring soluble TREM1 as a potential biomarker of treatment response

• Assessing changes in myeloid cell infiltration and polarization following TREM1-targeted therapy

Potential challenges and considerations:

• Identifying the optimal timing for TREM1 inhibition during cancer progression

• Developing combination strategies that address both TREM1-mediated myeloid suppression and other immune evasion mechanisms

• Balancing TREM1 inhibition to reduce tumor-promoting inflammation while preserving anti-tumor immune responses

Through comprehensive pan-cancer analysis, research has demonstrated that overexpression of TREM1 in tumors correlates closely with unfavorable outcomes, infiltration of immune-suppressive cells, and immune regulation, highlighting its potential as both a tumor prognostic biomarker and a novel target for cancer immunotherapy .

What are the most promising future directions in TREM1 research?

Based on current evidence, several promising research directions are emerging in the TREM1 field:

Mechanistic studies:

• Identification and characterization of endogenous TREM1 ligands, especially in non-infectious inflammatory conditions

• Deeper understanding of how TREM1 multimerization leads to signal transduction and amplification of inflammatory responses

• Elucidation of cell type-specific TREM1 regulation and function, particularly in neutrophils versus monocytes/macrophages

Therapeutic development:

• Design of more selective and potent TREM1 inhibitors based on structural insights into receptor-ligand interactions

• Development of tissue-targeted TREM1 inhibition strategies to enhance efficacy while reducing systemic effects

• Exploration of combination therapies that target TREM1 alongside other inflammatory or immune checkpoint pathways

Translational research:

• Validation of TREM1 as a biomarker for disease progression and treatment response across multiple conditions

• Standardization of methods for detecting and quantifying soluble TREM1 in clinical samples

• Prospective studies evaluating TREM1 inhibition in carefully selected patient populations based on disease mechanism and TREM1 expression

Disease-specific approaches:

• In cancer: investigating TREM1's role in shaping the tumor immune microenvironment and resistance to immunotherapy

• In cardiovascular disease: exploring TREM1's impact on lipid metabolism and foam cell formation

• In inflammatory disorders: defining the temporal window where TREM1 inhibition provides maximum benefit

Interdisciplinary integration:

• Combining genetics, cellular immunology, and systems biology approaches to comprehensively understand TREM1's role in health and disease

• Developing computational models that predict the impact of TREM1 modulation in complex disease environments

• Incorporating single-cell technologies to define TREM1 function in specific cellular subsets within heterogeneous tissues

Through these diverse research directions, a more complete understanding of TREM1 biology will emerge, potentially leading to novel diagnostic and therapeutic approaches for a wide range of inflammatory and malignant conditions.