Triggering receptor expressed on myeloid cells 1 (TREM1) is an immunoglobulin (Ig) superfamily transmembrane protein that, in humans, is encoded by the TREM1gene.[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]
Function
Monocyte-, macrophage- and neutrophil-mediated inflammatory responses can be stimulated via receptors such as G protein-linked 7-transmembrane receptors (such as FPR1), Fc receptors, CD14, TLRs (such as TLR4), and cytokine receptors. TREM1 amplifies TLR-induced inflammation by increasing production of inflammatory cytokines.[10] The ligand of TREM1 is unknown, however, bacterial infection, ischemic stroke and challenge with lipopolysaccharide or lipoteichoic acid were observed to increase TREM1 expression.[8] In granulocytes, C/EBPε induces TREM1 expression independently from inflammatory response.[11]
TREM1 forms a complex with transmembrane adaptor DAP12 and, upon TREM1 engagement, a protein tyrosine kinase Syk-mediated cascade of tyrosine phosphorylation is initiated, activating downstream mediators such as PLCγ, PI3K, and MAPK. This cascade promotes the release of inflammatory cytokines and/or chemokines by neutrophils and macrophages, as well as their migration.[12][13]
TREM1 expression is higher in tumor vs non-tumor tissues, likely due to its expression by myeloid cells that infiltrate tumors.[17][18] TREM1 is expressed by myeloid immune-suppressive cell populations such as monocytic myeloid-derived suppressor cells (mMDSC), tumor-associated neutrophils (TANs), and tumor associated macrophages (TAMs). These types of tumor-associated myeloid infiltrate correlate with shorter survival times of patients with solid tumors, and are likely to be the reason that not all tumors respond to checkpoint inhibitor therapy.[19][20] Antibodies that target TREM1 are therefore being studied for use in treatment patients with tumors that do not respond to checkpoint inhibitor therapy.
During inflammation, a soluble form of the molecule (sTREM1) accumulates in the circulation, and is a biomarker of inflammation. There is debate over whether sTREM1 is produced as a splice variant or as the results of proteolytic cleavage.[21][22] sTREM1 acts as a decoy for the unknown TREM1 ligands, and thereby prevents TREM1 activation.[23] sTREM1 has been studied as a biomarker of development of pneumonia, sepsis,[24] inflammatory bowel diseases,[25][26] and liver cirrhosis.[27]
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.[28] Male and female animals underwent a standardized phenotypic screen[29] to determine the effects of deletion.[30][31][32][33] Additional screens included immune phenotyping.[34] Blockade of TREM1 protects mice against microbe-induced shock, indicating that it is an important regulator of the immune response.[8]
Celsius Therapeutics is developing CEL383, an antibody inhibitor of TREM1, for treatment of inflammatory bowel disease. As of October 2023, CEL383 is being evaluated in a phase 1 trial in healthy volunteers.
^ abcBouchon A, Facchetti F, Weigand MA, Colonna M (April 2001). "TREM-1 amplifies inflammation and is a crucial mediator of septic shock". Nature. 410 (6832): 1103–7. doi:10.1038/35074114. PMID11323674. S2CID4403589.
^Tejera A, Santolaria F, Diez ML, Alemán-Valls MR, González-Reimers E, Martínez-Riera A, Milena-Abril A (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): 117–23. doi:10.1016/j.cyto.2007.05.002. PMID17659879.
^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): 1525–31. doi:10.1007/s10620-008-0514-5. PMID18975078. S2CID12356021.
^Jung YS, Park JJ, Kim SW, Hong SP, Kim TI, Kim WH, Cheon JH (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. PMID22721842.
^Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. S2CID85911512.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Kelker MS, Foss TR, Peti W, Teyton L, Kelly JW, Wüthrich K, Wilson IA (September 2004). "Crystal structure of human triggering receptor expressed on myeloid cells 1 (TREM-1) at 1.47 A". Journal of Molecular Biology. 342 (4): 1237–48. doi:10.1016/j.jmb.2004.07.089. PMID15351648.
Plachouras D, Routsi C, Giamarellos-Bourboulis EJ, Spyridaki E, Andrianakis I, Metzelopoulos S, et al. (2006). "Monocytes as a site of production of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in the septic host". Scandinavian Journal of Infectious Diseases. 38 (10): 909–15. doi:10.1080/00365540600786523. PMID17008237. S2CID7754570.
