TREM-1 (Triggering Receptor Expressed on Myeloid Cells) - Info

TREM-1 (Triggering Receptor Expressed on Myeloid Cells)

The innate immune system is considered as the first line of defense against infection. It targets a broad range of pathogens and requires the coordinated action of multiple cell types and serum proteins. The most important congenital effector cells include professional phagocytes (neutrophils and monocytes/macrophages) and natural killer cells (NK). They all have different receptors on the cell surface that recognize pathogens or endogenous molecules during tissue damage. The balance between activating and inhibitory signals generated by the activation of these receptors ultimately controls neutrophil and macrophage-mediated phagocytosis, the release of pro-inflammatory cytokines and the NK cell response.

The human TREM-1 is a 30 kDa glycoprotein of the immunoglobulin superfamily. It consists of a single extracellular immunoglobulin-like V-type domain, a transmembrane region with a charged residue, lysine and a short cytoplasmic tail. TREM-1 is expressed in late stages of myeloid cell differentiation and associated with DAP12 in terms of signaling and function. Activation of the TREM-1/DAP12 signaling pathway promotes the recruitment and activation of protein tyrosine kinases, resulting in the tyrosine phosphorylation of many protein species, Ca2 + mobilization, activation of extracellular signal-regulated kinases (ERK), and transcriptional complexes downstream of ERK.

Using a specific monoclonal antibody, it has been demonstrated that human TREM-1 is expressed on blood neutrophils and on CD14 monocytes/macrophages. In normal tissues TREM-1 is additionally selectively expressed in lung alveolar macrophages, which are specialized in the elimination of pathogens, apoptotic cells and macromolecules. This cell and tissue distribution suggests that TREM-1 plays a role in inflammatory reactions to infections. In fact, TREM-1 is highly expressed in infections of human skin and lymph nodes caused by bacteria and fungi. In these lesions, TREM-1 is expressed not only in neutrophil infiltrates but also in epithelial cells surrounding granulomatous reactions.

Most likely, TREM-1 recognizes a soluble protein or cell surface protein that is ex novo expressed or overexpressed due to inflammation and/or tissue damage. The role of TREM-1 as an inflammatory enhancer was confirmed in vivo in animal models of acute bacterial inflammation. In all of these models, hyperinflammatory responses and deaths are reduced by blocking TREM-1 signaling with a soluble TREM-1-IgG fusion protein. In contrast, DAP12 transgenic mice in which the TREM-1/DAP12-dependent signaling pathway is constitutively active regardless of the involvement of TREM-1 are very susceptible to LPS-induced shock. In addition, mice overexpressing DAP12 develop pneumonia due to massive infiltration of macrophages in the lung. Together, these results demonstrate a crucial role of TREM-1 in the initiation and enhancement of inflammatory responses. They also imply TREM-1 as a potential therapeutic target in diseases characterized by an excessive inflammatory response to infections such as septic shock and acute lung injury.

TREM-1 is highly conserved in mice and encoded in a syntenic region of chromosome 17. The mouse TREM cluster comprises TREM-1 and TREM-2 loci and an additional TREM-3 gene encoding a receptor that activates macrophage cell lines. The TREM gene cluster comprises several genes that code for both activating and inhibitory receptors, as do other immunoglobulins.

In summary, TREMs are an extended family of related receptors that include both activating and inhibiting isoforms and that regulate both innate and adaptive immune responses mediated by myeloid cells. It is important to study the genetics of this locus in humans (ie, the variability of gene numbers and the polymorphism of each gene). Although TREM-1 is primarily involved in innate responses, other TREMs can direct functions of myeloid cells involved in T cell stimulation and brain and bone homeostasis. The identification of TREM ligands is crucial for understanding their immune and non-immune functions.

Colonna M, Facchetti F (June 2003). "TREM-1 (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses". The Journal of Infectious Diseases. 187 Suppl 2: S397–401. doi:10.1086/374754