Disease relevance of TREM1

• In sharp contrast to the effect by Ad-FDAP12, transgene expression in the liver of soluble form of extracellular domain of TREM-1 as an antagonist of DAP12 signaling, remarkably inhibited zymosan A-induced granuloma formation at all time points examined [1].
• Notably, blockade of TREM-1 protects mice against LPS-induced shock, as well as microbial sepsis caused by live Escherichia coli or caecal ligation and puncture [2].
• TREM-1 amplifies inflammation and is a crucial mediator of septic shock [2].
• In primary human monocytes TREM-1 activation did not trigger innate antimicrobial pathways directed against intracellular Mycobacterium tuberculosis, and only minimally improved phagocytosis [3].
• Blockade of TREM-1 reduces inflammation and increases survival in animal models of bacterial infections that cause systemic hyperinflammatory syndromes [4].

Psychiatry related information on TREM1

• Breaths during REM sleep were divided into phasic (associated with eye movement, PREM) and tonic (not associated with eye movements, TREM) [5].

High impact information on TREM1

• TREM-1 is an activating receptor expressed at high levels on neutrophils and monocytes that infiltrate human tissues infected with bacteria [2].
• These results demonstrate a critical function of TREM-1 in acute inflammatory responses to bacteria and implicate TREM-1 as a potential therapeutic target for septic shock [2].
• Other TREM proteins regulate the differentiation and function of macrophages, microglia, dendritic cells, osteoclasts and platelets [6].
• TREM proteins are a family of cell surface receptors that participate in diverse cell processes, including inflammation, bone homeostasis, neurological development and coagulation [6].
• Together these data show that that TLT-1 does not function to inhibit members of the TREM family but instead may play a role in maintaining vascular hemostasis and regulating coagulation and inflammation at sites of injury [7].

Biological context of TREM1

• Monocytes displayed a gradual up-regulation of TREM-1 upon LPS in vivo and in vitro [8].
• By analyzing receptor-induced tyrosine phosphorylation patterns, we discovered that the ligation of TREM-1 leads to tyrosine phosphorylation of the non-T cell activation linker (NTAL; also called linker of activation in B cells or LAB) in a myelomonocytic cell line and primary human granulocytes [9].
• These results give a new perspective for the regulation of neutrophil inflammatory responses emphasizing the importance of TREM-1 in innate immunity [10].
• Activation via TREM-1 induces immediate degranulation of neutrophilic granules resulting in the release of IL-8, respiratory burst, and phagocytosis [10].
• For signal transduction, TREM-1 couples to the ITAM-containing adapter DNAX activation protein of 12 kDa (DAP12) [9].

Anatomical context of TREM1

• TREM1 triggers phagocyte secretion of pro-inflammatory chemokines and cytokines, amplifying the inflammation that is induced by bacteria and fungi [11].
• Thus, TREM-1 mediates activation of neutrophil and monocytes, and may have a predominant role in inflammatory responses [12].
• We have identified new activating receptors of the Ig superfamily expressed on human myeloid cells, called TREM (triggering receptor expressed on myeloid cells) [12].
• A TREM family member, TLT-1, is found exclusively in the alpha-granules of megakaryocytes and platelets [7].
• The engagement of triggering receptor expressed on myeloid cells 1 (TREM-1) on macrophages and neutrophils leads to TNF-alpha and IL-8 production and enhances inflammatory responses to microbial products [9].

Associations of TREM1 with chemical compounds

• In addition, low levels of NTAL are correlated with decreased and delayed mobilization of Ca(2+) after TREM-1 triggering [9].
• Up-regulation of TREM-1 expression was specific to PGE(2) among arachidonic acid metabolites, while ligands for chemoattractant receptor-homologous molecule expressed on Th2 cells and the thomboxane-like prostanoid receptor failed to induce mTREM-1 expression [13].
• Here we have shown that in monocytes TREM-1 mRNA levels, measured by reverse transcription-polymerase chain reaction (RT-PCR), remained unchanged and TREM-1 protein levels, measured by flow cytometry, increased, indicating that LPS increases TREM-1 expression by a post-transcriptional mechanism [14].

Regulatory relationships of TREM1

• The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44 [15].
• Activation of TREM-1 expressed on PGE(2)-pretreated PBMC by an agonistic TREM-1 mAb significantly enhanced the production of IL-8 and TNF-alpha [13].

Other interactions of TREM1

• To mediate activation, TREM-1 associates with the transmembrane adapter molecule DAP12 [12].
• Nonbacterial TLR ligands such as polyinosine-polycytidylic acid and imidazoquinoline, as well as the TLR9 ligand CpG, did not impact TREM-1 expression [8].
• Functionally, primary monocytes differentiated into immature dendritic cells following activation through TREM-1, evidenced by higher expression of CD1a, CD86, and MHC class II molecules [3].
• (i) Spliced mRNAs encoding soluble forms of TREM-1 and TREM-2 (recently discovered inflammatory-signal-amplifying receptors) were regulated by BCG-CWS, resulting in their differential expression [16].
• TREM-1 and MDL-1 RNA expression was also more elevated in adult than fetal tissues and in normal than malignant cells [17].

Analytical, diagnostic and therapeutic context of TREM1

• With the additional use of analytical ultracentrifugation and 1H NMR spectroscopy of both human and mouse TREM-1, we have conclusively demonstrated the monomeric state of this extracellular ectodomain in solution and, presumably, of the TREM family in general [18].
• METHODS: Using flow cytometry, we examined the surface expression of TREM-1 and HLA-DR in peripheral blood monocytes from 11 septic patients, 7 elective gastrointestinal surgical patients, and 10 healthy volunteers. svTREM-1 levels were analyzed by RT-PCR [19].
• METHODS: Using the reverse transcription polymerase chain reaction (RT-PCR), we examined the expression of TREM-1 mRNA in 10 cases of mild acute pancreatitis (MAP), 8 cases of severe acute pancreatitis (SAP), and 10 cases of healthy control subjects [20].
• Soluble TREM-1 levels were measured by an enzyme-linked immunosorbent assay [21].
• To investigate the differential expression of TREM-1 in lung infections, its levels were assessed in bronchoalveolar lavage specimens from patients with community-acquired pneumonia or tuberculosis [22].

References