TREM1
Protein-coding gene in the species Homo sapiens
From Wikipedia, the free encyclopedia
Triggering receptor expressed on myeloid cells 1 (TREM1) is an immunoglobulin (Ig) superfamily transmembrane protein that, in humans, is encoded by the TREM1 gene.[5][6][7] TREM1 is constitutively expressed on the surface of peripheral blood monocytes and neutrophils, and upregulated by toll-like receptor (TLR) ligands; activation of TREM1 amplifies immune responses.[6][8][9]
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| Aliases | TREM1, CD354, TREM-1, triggering receptor expressed on myeloid cells 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 605085; MGI: 1930005; HomoloGene: 10243; GeneCards: TREM1; OMA:TREM1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Gene
TREM1 expression is inducible and regulated by inflammatory and lineage-specific signals. Bacterial infection, ischemic stroke, and exposure to lipopolysaccharide or lipoteichoic acid increase TREM1 expression.[8] In granulocytes, expression of TREM1 is induced by C/EBPε independently of inflammatory signaling pathways.[10]
Structure
TREM1 is a cell surface receptor that functions in association with the transmembrane adaptor protein DAP12. Upon receptor engagement, the TREM1–DAP12 complex initiates intracellular signaling through phosphorylation-dependent pathways.[11][12]
During inflammation, a soluble form of the receptor (sTREM1) accumulates in circulation. The origin of sTREM1 remains debated and may involve either alternative splicing or proteolytic cleavage of membrane-bound TREM1.[13][14] Soluble TREM1 acts as a decoy receptor for TREM1 ligands and thereby inhibits receptor activation.[15]
Function
Monocyte-, macrophage-, and neutrophil-mediated inflammatory responses can be stimulated through receptors including G protein-linked 7-transmembrane receptors (such as FPR1), Fc receptors, CD14, Toll-like receptors (such as TLR4), and cytokine receptors. TREM1 functions primarily as an amplifier of TLR-induced inflammatory responses by increasing production of inflammatory cytokines.[16]
Although the endogenous ligand of TREM1 remains unknown, receptor activation triggers signaling through Syk, leading to activation of downstream effectors including PLCγ, PI3K, and MAPK. These pathways promote cytokine and chemokine release by neutrophils and macrophages and enhance migration of these cells.[11][12]
Clinical significance
Based on laboratory studies, TREM1 signaling has been implicated in the development of atherosclerosis,[17] non-alcoholic fatty liver disease (NAFLD),[18] and ischemic stroke.[12]
Cancer
TREM1 expression is elevated in tumor tissue relative to non-tumor tissue, likely reflecting expression by infiltrating myeloid cells.[19][20] TREM1 is expressed by immunosuppressive myeloid populations including monocytic myeloid-derived suppressor cells (mMDSCs), tumor-associated neutrophils (TANs), and tumor-associated macrophages (TAMs). These infiltrating populations are associated with reduced survival in patients with solid tumors and may contribute to resistance to checkpoint inhibitor therapy.[21][22]
Flow cytometric analyses of human tumor specimens from breast, bladder, endometrial, head and neck, ovarian, prostate, and renal cancers demonstrated enrichment of TREM1 expression within tumor-associated myeloid subsets including mMDSCs, TANs, and TAMs.[23] Single-cell immune profiling of stage III-C ovarian tumors identified TREM1 expression predominantly in TAMs and monocytes.[24] Additional studies also reported elevated TREM1 protein and TREM1 mRNA expression in tumor-associated myeloid populations.[25]
Higher TREM1 mRNA levels in tumors correlate with shorter survival in patients with colon cancer, breast cancer, pancreatic cancer, and squamous cell carcinoma.[24] Consequently, therapeutic strategies including TREM1-targeting antibodies are being investigated to improve responses in tumors resistant to checkpoint inhibition.
Biomarker applications
Circulating sTREM1 has been investigated as a biomarker of inflammatory activity and disease progression in pneumonia, sepsis,[26] inflammatory bowel disease,[27][28] and liver cirrhosis.[29]
As a drug target
TREM1 has emerged as a promising therapeutic target because of its role as an amplifier of innate immune and inflammatory responses rather than a primary initiator. TREM1 is expressed mainly on neutrophils, monocytes, macrophages, and microglia, where it potentiates signaling through pathways such as DAP12, SYK, NF-κB, MAPK, and PI3K/AKT, leading to increased production of pro-inflammatory cytokines and chemokines.[30][31] Because excessive TREM1 activation contributes to pathological inflammation across multiple diseases, therapeutic inhibition has been proposed as a strategy to dampen tissue damage while preserving essential host defense mechanisms.[30][31]
Preclinical and early translational studies have implicated TREM1 targeting in a broad range of indications including cancer, sepsis, inflammatory bowel disease, atherosclerosis, liver diseases, neurological disorders, stroke, and pain-related conditions.[30][32][33][34][35][36][37] In oncology, TREM1 signaling is associated with an immunosuppressive tumor microenvironment and disease progression, while in neuroinflammatory conditions it mediates pathogenic microglia–immune interactions linked to neurodegeneration and cognitive dysfunction.[30][38] Therapeutic approaches under investigation include inhibitory peptides, monoclonal antibodies, soluble decoy receptors, and nanomedicine-based delivery systems designed to selectively suppress TREM1 activity and restore immune homeostasis.[31][30]
Model organisms
Model organisms have been used in the study of TREM1 function. A conditional knockout mouse line called Trem1tm1(KOMP)Vlcg was generated at the Wellcome Trust Sanger Institute.[39] Male and female animals underwent a standardized phenotypic screen[40] to determine the effects of deletion.[41][42][43][44] Additional screens included immune phenotyping.[45] Blockade of TREM1 protects mice against microbe-induced shock, indicating that it is an important regulator of the immune response.[8]