Monocyte/macrophage- and neutrophil-mediated inflammatory responses can be stimulated through a variety of receptors, including G protein-linked 7-transmembrane receptors (e.g., FPR1; 136537), Fc receptors (see 146790), CD14 (158120) and Toll-like receptors (e.g., TLR4; 603030), and cytokine receptors (e.g., IFNGR1; 107470). Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to the Ig superfamily, such as TREM1, or to the C-type lectin superfamily. Depending on their transmembrane and cytoplasmic sequence structure, these receptors have either activating (e.g., KIR2DS1; 604952) or inhibitory functions (e.g., KIR2DL1; 604936). TREM1 is an activating receptor that is expressed on monocytes and neutrophils (Bouchon et al., 2000).

By searching an EST database with NKp44 (LY95; 604531) as the probe, Bouchon et al. (2000) identified cDNAs encoding TREM1 (triggering receptor expressed on myeloid cells-1). Sequence analysis predicted that the 234-amino acid TREM1 protein begins with a hydrophobic signal peptide, followed by an extracellular region containing a single V-type Ig domain with 3 potential N-glycosylation sites; a transmembrane stretch with a charged lysine residue; and a 5-amino acid cytoplasmic tail with no signaling motifs. RT-PCR and fluorescence-activated cell sorter (FACS) analysis detected TREM1 expression in monocytes and neutrophils but not in lymphocytes, dendritic cells, or other cell types. Immunoprecipitation analysis demonstrated that TREM1 is a 30-kD glycoprotein that is reduced to 26 kD by deglycosylation, in agreement with the predicted molecular mass.

Bouchon et al. (2000) found that expression of TREM1 was upregulated by stimulation with lipopolysaccharide (LPS), gram-negative bacteria, and fungi. Cross-linking of TREM1 on neutrophils induced interleukin-8 (IL8; 146930) and myeloperoxidase (606989) secretion, while cross-linking on monocytes induced not only secretion of IL8 but also of monocyte chemotactic protein-1 (MCP1, or SCYA2; 158105) and tumor necrosis factor (TNF; 191160); MCP1 and TNF secretion could be further upregulated by LPS-mediated priming. TREM1 engagement also induced upregulation of adhesion molecules (e.g., ITGB1; 135630) and costimulatory molecules (e.g., CD40; 109535). Taken together, the expression and functional properties of TREM1 suggested a role in acute inflammation. Immunoblot analysis showed that TREM1 is associated with DAP12 (TYROBP; 604142), a molecule frequently associated with activating receptors.

Using flow cytometric analysis, Bouchon et al. (2001) demonstrated that TREM1 expression is upregulated in neutrophils and monocytes by extracellular, but not intracellular, bacteria or their fatty acid products. Immunohistochemical analysis revealed high expression in neutrophils associated with skin lesions caused by bacteria and by fungus, with expression also observed in epithelioid and multinucleated giant cells in the latter. Likewise, expression was strongly increased in neutrophils isolated from the peritoneal cavity of patients or mice with bacterial septic shock. In contrast, expression was normal in nonmicrobial inflammatory lesions.

Read et al. (2015) found that stimulation of human neutrophils with a mixture of TLR ligands triggered TREM1 in a reporter cell line, whereas stimulation with TLR ligands in the absence of neutrophils failed to induce TREM1 activation. Peptidoglycan (PGN) turned out to be the critical TLR ligand for TREM1 induction. Mass spectrometric and immunoprecipitation analyses identified PGLYRP1 (604963) as the TREM1-stimulating protein on neutrophils cultured with PGN. Addition of PGLYRP1 to PGN enabled PGN recognition by TREM1. Blockade of either TREM1 or PGLYRP1 inhibited IL8 (146930) release. Surface plasmon resonance analysis indicated that PGN enhanced and stabilized the interaction of TREM1 with PGLYRP1. Activation of TREM1 by PGLYRP1 required multimeric PGN. In the absence of bacterial products, TREM1 on myeloid cells could also be activated by multimeric PGLYRP1.

Nguyen-Lefebvre et al. (2018) induced hepatic fibrosis in mice by carbon tetrachloride (CCl4) administration and found that Trem1 -/- mice showed significantly less fibrosis than wildtype mice and, correspondingly, that Trem1 -/- mice showed significantly lower expression of fibrogenic genes that are upregulated in hepatic fibrosis than wildtype mice. Transcript levels of genes downregulated in activated hepatic stellate cells (HSCs) were lower in CCl4-treated wildtype mice than in Trem1 -/- mice, confirming that Trem1 is essential for the activation of HSCs. Further analysis revealed that Trem1 enhances hepatic inflammation and is essential for the recruitment and differentiation of monocyte-derived macrophages during hepatic fibrogenesis. Examination of the early stage of CCl4-induced liver injury in wildtype and Trem1 -/- mice demonstrated that Trem1 controls the mobilization, recruitment, and differentiation of inflammatory cells in response to injury and consequently enhances liver damage. Quantitative RT-PCR showed that Trem1 expression in liver and the profibrogenic signature of activated Kupffer cells increase during fibrogenesis, and adoptive transfer of Trem1-sufficient Kupffer cells into Trem1-deficient mice reconstituted the recruitment of inflammatory monocytes and the severity of liver injury. Analysis of fibrosis biomarkers, TREM1 expression, and phenotype in liver tissues from patients with hepatic fibrosis showed that human liver fibrosis is associated with the recruitment and differentiation of TREM1-positive Kupffer cells and monocytes and monocyte-derived macrophages.

By genomic sequence analysis, Allcock et al. (2003) determined that all genes in the TREM cluster have an exon encoding the 5-prime UTR and leader peptide, a second exon encoding the IgV domain, and a variable number of downstream exons encoding the stalk, transmembrane, and cytoplasmic regions. TREM1 contains 4 exons. A soluble splice variant of TREM1 lacks exon 3, which encodes the transmembrane region.

By somatic cell hybrid analysis, Bouchon et al. (2000) mapped the TREM1 and TREM2 (605086) genes to chromosome 6, where LY95 is located. By genomic sequence analysis, Allcock et al. (2003) mapped the TREM1 gene to chromosome 6p21.1, within a TREM gene cluster. The mouse Trem1 gene maps to chromosome 17 in a region that shows homology of synteny to human chromosome 6.

Bouchon et al. (2001) found that, in a mouse model, pretreatment with Trem1 led to survival in most animals challenged with lipopolysaccharide. Pretreatment lowered systemic levels of Tnfa and IL1b (147720) and reduced cellular infiltrates without causing leukopenia. Pretreatment also conferred significant protection against lethal bacterial peritonitis, whereas treatment with Tnfr1 (191190) caused accelerated death of all animals. Treatment of mice up to 4 hours after lipopolysaccharide injection was still protective against endotoxic shock, suggesting to the authors that soluble TREM1 treatment might be a suitable therapeutic tool in the treatment of septic shock and other microbial-mediated diseases.