Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCVFEE6)

• DOT Name: Triggering receptor expressed on myeloid cells 1 (TREM1)
• Synonyms: TREM-1; Triggering receptor expressed on monocytes 1; CD antigen CD354
• Gene Name: TREM1
• UniProt ID: TREM1_HUMAN
• PDB ID: 1Q8M; 1SMO
• Pfam ID: PF07686
• Sequence:
  MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRD
  GEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPK
  EPHMLFDRIRLVVTKGFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKST
  ADVSTPDSEINLTNVTDIIRVPVFNIVILLAGGFLSKSLVFSVLFAVTLRSFVP
• Function: [Isoform 1]: Cell surface receptor that plays important roles in innate and adaptive immunity by amplifying inflammatory responses. Upon activation by various ligands such as PGLYRP1, HMGB1 or HSP70, multimerizes and forms a complex with transmembrane adapter TYROBP/DAP12. In turn, initiates a SYK-mediated cascade of tyrosine phosphorylation, activating multiple downstream mediators such as BTK, MAPK1, MAPK3 or phospholipase C-gamma. This cascade promotes the neutrophil- and macrophage-mediated release of pro-inflammatory cytokines and/or chemokines, as well as their migration and thereby amplifies inflammatory responses that are triggered by bacterial and fungal infections. By also promoting the amplification of inflammatory signals that are initially triggered by Toll-like receptor (TLR) and NOD-like receptor engagement, plays a major role in the pathophysiology of acute and chronic inflammatory diseases of different etiologies including septic shock and atherosclerosis ; [Isoform 2]: Acts as a decoy receptor, counterbalancing TREM1 pro-inflammatory activity through the neutralization of its lignad.
• Tissue Specificity: Mostly expressed by immune cells of the myeloid lineage, such as monocytes, macrophages, neutrophils and dendritic cells . Expression is associated with a mature stage of myeloid development . Highly expressed in adult liver, lung and spleen than in corresponding fetal tissue. Also expressed in the lymph node, placenta, spinal cord and heart tissues. Isoform 2 was detected in the lung, liver and mature monocytes.
• Reactome Pathway:
  Cell surface interactions at the vascular wall (R-HSA-202733)
  DAP12 interactions (R-HSA-2172127)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[4]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[5]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[6]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[7]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[9]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[10]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[8]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Triggering receptor expressed on myeloid cells 1 (TREM1).	[11]

References

• [1] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [5] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [6] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [7] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [8] Preliminary discovery of novel markers for human cell line activation test (h-CLAT). Toxicol In Vitro. 2021 Aug;74:105154. doi: 10.1016/j.tiv.2021.105154. Epub 2021 Mar 25.
• [9] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [10] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [11] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.