TREM1 - triggering receptor expressed on myeloid cells 1 |Elisa - Clia - Antibody - Protein

Background

Triggering receptor expressed on myeloid cells 1 (TREM1) is an immunoglobulin (Ig) superfamily receptor predominantly expressed on myeloid cells, such as neutrophils, monocytes, macrophages, and dendritic cells. TREM1 is recognized for its role in amplifying inflammatory responses during infections and other inflammatory conditions, and it plays a significant part in innate immune regulation. TREM1 is a potent activator of inflammatory responses and is known to amplify signaling from pattern recognition receptors (PRRs) such as toll-like receptors (TLRs). Through these amplifying actions, TREM1 enhances the immune system’s ability to clear pathogens but also has the potential to contribute to pathological inflammation.

TREM1 activation is linked with inflammatory cytokine production, chemotaxis, and cellular responses involved in pathogen clearance. In addition to pathogen responses, TREM1 is implicated in sterile inflammation, where it is upregulated during non-infectious inflammation, such as that observed in autoimmune diseases, cancer, and tissue damage. Its role in amplifying inflammatory cascades makes TREM1 a focal point for research into immune regulation and as a therapeutic target for controlling inflammation-related diseases.

Protein Structure

TREM1 is a single-pass type I transmembrane receptor consisting of approximately 230 amino acids. Its structure is characterized by three primary domains:

Extracellular Domain:

• The extracellular domain of TREM1 contains a single Ig-like V-type domain, typical of receptors in the Ig superfamily. This domain enables ligand binding and recognition of microbial molecules and endogenous ligands.
• Structural studies indicate that the Ig-like V-type domain in TREM1 provides the receptor with the ability to bind various ligands, though its exact ligands remain somewhat unclear. It is suspected that TREM1 interacts with both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) for immune signaling.
• The extracellular domain also contains sites for glycosylation, which contribute to structural stability, correct protein folding, and receptor-ligand interactions.

Transmembrane Domain:

• TREM1 has a hydrophobic transmembrane region that anchors it within the cell membrane. This domain interacts with the adaptor protein DAP12 (DNAX activation protein of 12 kDa), which is essential for downstream signaling.
• Through a positively charged lysine residue within its transmembrane domain, TREM1 forms a stable association with DAP12. This interaction enables TREM1 to transmit activation signals into the cell, which are mediated by DAP12’s immunoreceptor tyrosine-based activation motifs (ITAMs).

Cytoplasmic (Intracellular) Domain:

• The intracellular domain of TREM1 is relatively short and lacks intrinsic signaling motifs such as ITAMs. Instead, TREM1 relies on DAP12’s ITAMs to initiate downstream signaling cascades.
• When TREM1 binds to a ligand, it triggers DAP12 phosphorylation, which activates signaling pathways involving spleen tyrosine kinase (Syk) and other downstream kinases. These signaling events ultimately lead to the production of pro-inflammatory cytokines and chemokines, which amplify immune responses.

Classification and Subtypes

TREM1 belongs to the TREM family within the immunoglobulin superfamily. The TREM family includes TREM1, TREM2, and other related receptors that regulate immune responses by activating or inhibiting signaling pathways in myeloid cells. While TREM1 is primarily involved in amplifying inflammation, TREM2 is associated with immune regulation and anti-inflammatory signaling, particularly in microglial cells within the central nervous system.

TREM1 does not have known isoforms or subtypes in humans, although its expression and activity may be regulated differently depending on cell type and tissue context. TREM1's structure and function are highly conserved among mammals, highlighting its essential role in innate immunity across species.

Function and Biological Significance

TREM1 is a major amplifier of inflammatory responses in myeloid cells. Its functions and biological significance can be summarized as follows:

Amplification of Inflammatory Responses:

• TREM1 is activated by binding to microbial PAMPs or endogenous DAMPs, and its activation enhances cytokine and chemokine production. This results in an intensified immune response, particularly during infections. TREM1 is known to synergize with TLRs, particularly TLR4, amplifying the signaling cascades initiated by these PRRs.
• When TREM1 is activated, it triggers the release of cytokines such as TNF-α, IL-6, and IL-1β, as well as chemokines like CXCL8, which promote the recruitment of additional immune cells to infection sites. This amplification helps in pathogen clearance but can also lead to excessive inflammation if not properly regulated.

Role in Innate Immune Cell Activation:

• TREM1 contributes to the activation of neutrophils, monocytes, and macrophages, enhancing their phagocytic abilities and ROS production. This makes TREM1 essential for effective pathogen clearance and host defense mechanisms.
• In neutrophils, TREM1 activation promotes degranulation and the release of antimicrobial peptides, while in macrophages, it enhances phagocytosis and intracellular killing of pathogens.

Modulation of Sterile Inflammation:

• TREM1 is not only involved in microbial infections but also plays a role in sterile inflammation, which occurs in the absence of pathogens. During tissue damage or cellular stress, TREM1 can be activated by endogenous ligands (DAMPs), which leads to the production of pro-inflammatory cytokines.
• In diseases such as atherosclerosis, cancer, and autoimmune disorders, TREM1 is upregulated and contributes to inflammation, sometimes exacerbating tissue damage. This has made TREM1 a therapeutic target in conditions where excessive sterile inflammation is detrimental to tissue function and patient outcomes.

Synergy with Other Immune Receptors:

• TREM1 often works in synergy with TLRs and other PRRs to boost immune responses. This cooperation allows TREM1 to enhance TLR-mediated signaling pathways, resulting in heightened cytokine production and immune cell recruitment.
• By acting as a co-receptor, TREM1 amplifies the immune cell responses, promoting efficient pathogen detection and clearance. However, this synergy can also contribute to pathological inflammation if left unchecked.

Clinical Issues

Sepsis and Severe Infections:

• TREM1 has been extensively studied in the context of sepsis, where its role in amplifying inflammatory responses is particularly evident. In septic patients, TREM1 is upregulated, and its activation correlates with increased cytokine production and inflammatory responses. High TREM1 expression has been associated with poor outcomes in sepsis, and thus, TREM1 inhibition is being explored as a therapeutic strategy to modulate inflammation without compromising immune defense.

Chronic Inflammatory Diseases:

• In chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and atherosclerosis, TREM1 is upregulated and contributes to sustained inflammation. Blocking TREM1 signaling in animal models of these diseases has shown promise in reducing inflammation and improving outcomes, highlighting TREM1’s role in chronic inflammatory pathologies.

Cancer:

• TREM1 expression is elevated in the tumor microenvironment, where it can contribute to the inflammatory milieu that supports tumor growth. TREM1-positive macrophages have been found in several types of tumors, and their presence is often associated with poor prognosis. Modulating TREM1 signaling is being investigated as a strategy to alter the tumor microenvironment and potentially enhance antitumor immune responses.

Cardiovascular Diseases:

• TREM1 has been implicated in atherosclerosis and cardiovascular disease. It is expressed in atherosclerotic plaques and is associated with inflammation within the vascular system. Studies indicate that TREM1 signaling promotes the progression of atherosclerosis by increasing inflammation within plaques, contributing to plaque instability and the risk of cardiovascular events.

Summary

TREM1 is a member of the immunoglobulin superfamily that plays a critical role in amplifying inflammatory responses in myeloid cells. It has a distinct protein structure that includes an extracellular Ig-like domain, a transmembrane region that interacts with the DAP12 adaptor, and a short intracellular tail that relies on DAP12 for signaling. This interaction with DAP12 activates signaling pathways that lead to the production of inflammatory cytokines and chemokines, amplifying responses to pathogens and contributing to the recruitment and activation of immune cells.

Functionally, TREM1 is central to the regulation of inflammation, particularly during infections and sterile inflammatory conditions. Its role in amplifying responses places it at the core of several inflammatory diseases, where excessive TREM1 activity is associated with adverse outcomes. In sepsis, chronic inflammatory diseases, cancer, and cardiovascular diseases, TREM1’s amplification of immune responses can lead to tissue damage, suggesting its potential as a therapeutic target. Consequently, modulation of TREM1 activity is being investigated to manage inflammation-related diseases, aiming to balance effective immune responses with the prevention of pathological inflammation.