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TREM1

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TREM1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTREM1, CD354, TREM-1, triggering receptor expressed on myeloid cells 1
External IDsOMIM: 605085; MGI: 1930005; HomoloGene: 10243; GeneCards: TREM1; OMA:TREM1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

54210

58217

Ensembl

ENSG00000124731

ENSMUSG00000042265

UniProt

Q9NP99

Q9JKE2

RefSeq (mRNA)

NM_001242589
NM_001242590
NM_018643

NM_021406
NM_001347399

RefSeq (protein)

NP_001229518
NP_001229519
NP_061113

NP_001334328
NP_067381

Location (UCSC)Chr 6: 41.27 – 41.29 MbChr 17: 48.54 – 48.55 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

Gene

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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

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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

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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

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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

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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

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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

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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

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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]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000124731 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000042265 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Gingras MC, Lapillonne H, Margolin JF (March 2002). "TREM-1, MDL-1, and DAP12 expression is associated with a mature stage of myeloid development". Molecular Immunology. 38 (11): 817–824. doi:10.1016/S0161-5890(02)00004-4. PMID 11922939.
  6. ^ a b Bouchon A, Dietrich J, Colonna M (May 2000). "Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes". Journal of Immunology. 164 (10). Baltimore: 4991–4995. doi:10.4049/jimmunol.164.10.4991. PMID 10799849.
  7. ^ "Entrez Gene: TREM1 triggering receptor expressed on myeloid cells 1".
  8. ^ a b c Bouchon A, Facchetti F, Weigand MA, Colonna M (April 2001). "TREM-1 amplifies inflammation and is a crucial mediator of septic shock". Nature. 410 (6832): 1103–1107. doi:10.1038/35074114. PMID 11323674. S2CID 4403589.
  9. ^ Mabbott NA, Baillie JK, Brown H, Freeman TC, Hume DA (September 2013). "An expression atlas of human primary cells: inference of gene function from coexpression networks". BMC Genomics. 14 (1): 632. doi:10.1186/1471-2164-14-632. PMC 3849585. PMID 24053356.
  10. ^ Suh HC, Benoukraf T, Shyamsunder P, Yin T, Cao Q, Said J, et al. (April 2017). "LPS independent activation of the pro-inflammatory receptor Trem1 by C/EBPε in granulocytes". Scientific Reports. 7 46440. Bibcode:2017NatSR...746440S. doi:10.1038/srep46440. PMC 5404328. PMID 28440307.
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  18. ^ Rao S, Huang J, Shen Z, Xiang C, Zhang M, Lu X (February 2019). "Inhibition of TREM-1 attenuates inflammation and lipid accumulation in diet-induced nonalcoholic fatty liver disease". Journal of Cellular Biochemistry. 120 (7): 11867–11877. doi:10.1002/jcb.28468. PMC 6593463. PMID 30805986.
  19. ^ Broz ML, Binnewies M, Boldajipour B, Nelson AE, Pollack JL, Erle DJ, et al. (November 2014). "Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity". Cancer Cell. 26 (5): 638–652. doi:10.1016/j.ccell.2014.09.007. PMC 4254577. PMID 25446897.
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  21. ^ Awad RM, De Vlaeminck Y, Maebe J, Goyvaerts C, Breckpot K (2018). "Turn Back the TIMe: Targeting Tumor Infiltrating Myeloid Cells to Revert Cancer Progression". Frontiers in Immunology. 9 1977. doi:10.3389/fimmu.2018.01977. PMC 6127274. PMID 30233579.
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  23. ^ Juric V, Chan C, Mayes E, Norng M, Le T, Dash S, et al. (December 2019). "Abstract C105: Targeting of TREM1+ myeloid cells to promote antitumor immunity" (PDF). Molecular Cancer Therapeutics. 18 (12_Supplement). Archived from the original (PDF) on 26 November 2020.
  24. ^ a b Mayes E, Juric V, Binnewies M, Canaday P, Lee T, Dash S, et al. (December 2021). "Abstract P104: Therapeutic targeting of TREM1 with PY159 promotes myeloid cell reprogramming and unleashes anti-tumor immunity" (PDF). Molecular Cancer Therapeutics. 20 (12_Supplement). Archived from the original (PDF) on 7 May 2024.
  25. ^ Immunotherapy of Cancer Conference (ITOC) 2021 Abstract P02.11, Society for the Immunotherapy of Cancer (SITC) Conference 2021, Poster 859
  26. ^ Tejera A, Santolaria F, Diez ML, Alemán-Valls MR, González-Reimers E, Martínez-Riera A, et al. (June 2007). "Prognosis of community acquired pneumonia (CAP): value of triggering receptor expressed on myeloid cells-1 (TREM-1) and other mediators of the inflammatory response". Cytokine. 38 (3): 117–123. doi:10.1016/j.cyto.2007.05.002. PMID 17659879.
  27. ^ Park JJ, Cheon JH, Kim BY, Kim DH, Kim ES, Kim TI, et al. (July 2009). "Correlation of serum-soluble triggering receptor expressed on myeloid cells-1 with clinical disease activity in inflammatory bowel disease". Digestive Diseases and Sciences. 54 (7): 1525–1531. doi:10.1007/s10620-008-0514-5. PMID 18975078. S2CID 12356021.
  28. ^ Jung YS, Park JJ, Kim SW, Hong SP, Kim TI, Kim WH, et al. (November 2012). "Correlation between soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) expression and endoscopic activity in inflammatory bowel diseases". Digestive and Liver Disease. 44 (11): 897–903. doi:10.1016/j.dld.2012.05.011. PMID 22721842.
  29. ^ Tornai D, Vitalis Z, Jonas A, Janka T, Foldi I, Tornai T, et al. (March 2021). "Increased sTREM-1 levels identify cirrhotic patients with bacterial infection and predict their 90-day mortality". Clinics and Research in Hepatology and Gastroenterology. 45 (5) 101579. doi:10.1016/j.clinre.2020.11.009. PMID 33773436.
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  31. ^ a b c Siskind S, Brenner M, Wang P (2022). "TREM-1 Modulation Strategies for Sepsis". Frontiers in Immunology. 13 907387. doi:10.3389/fimmu.2022.907387. PMC 9240770. PMID 35784361.
  32. ^ Sun H, Feng J, Tang L (December 2020). "Function of TREM1 and TREM2 in Liver-Related Diseases". Cells. 9 (12). doi:10.3390/cells9122626. PMC 7762355. PMID 33297569.
  33. ^ Vinolo E, Maillefer M, Jolly L, Colné N, Meiffren G, Carrasco K, et al. (2024). "The potential of targeting TREM-1 in IBD". Advances in Pharmacology. 101. San Diego, Calif.: 301–330. doi:10.1016/bs.apha.2024.10.010. PMID 39521605.
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Further reading

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