TREM1 Pathway
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TREM1 Pathway
TREMs (Triggering Receptor Expressed on Myeloid Cells) are a family of recently discovered receptors of the immunoglobulin superfamily, expressed on various cells of the myeloid lineage, which play important roles in innate immune responses, such as to activate inflammatory responses and to contribute to septic shock in response to microbial-mediated infections (Ref.1). During the onset of an infection, the host must launch a rapid innate response to control pathogen proliferation and spread the same until the adaptive response of specific T- and B-Cells has fully developed. This first line of defence is provided by the coordinate action of several effector cell types, including the phagocytes. These cells express a large array of cell-surface receptors, some of which detect pathogens and trigger responses to infectious and/or inflammatory stimuli (Ref.2). TREM1, the best-characterized TREM, regulates the function of myeloid cells in innate and adaptive responses (Ref.3). It is an activating receptor expressed at high levels on neutrophils and monocytes/macrophages that infiltrate human tissues infected with bacteria and fungi. Inflammatory responses to microbial products are amplified by a pathway mediated by TREM1 signaling through the adapter protein DAP12 (DNAX-Activation Protein-12), and thus represents a potential therapeutic target (Ref.4).

Human TREM1 is a 30-kDa glycoprotein of the immunoglobulin superfamily. It consists of a single extracellular immunoglobulin-like domain of the V-type, a transmembrane region with a charged residue, lysine, and a short cytoplasmic tail (Ref.4). The short intracellular tail of TREM1 presumably cannot transduce a signal. However, via a charged residue in its transmembrane domain, TREM1 interacts noncovalently with DAP12, a member of the C-type lectin superfamily that contains an intracellular ITAM (Immune Receptor Tyrosine-Based Activating Motif) (Ref.5). Generally, TREM1 is expressed at late stages of myeloid cell differentiation. In normal tissues, TREM1 is selectively expressed in lung alveolar macrophages, which specialize in the clearance of pathogens, apoptotic cells, and macromolecules (Ref.1). Human tissues infected with bacteria or fungi are infiltrated with neutrophils and monocytes that express high levels of TREM1. The expression of TREM1 is greatly upregulated in the presence of bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus or fungi such as Aspergillus fumigatus (Ref.6). Althogh TREM1 expression is upregulated by stimulation with LPS (Lipopolysaccharide), LTA (Lipoteichoic Acid), extracellular bacteria and fungi (Ref.7), the exact ligands for TREM1 are yet to be identified (Ref.4). Regardless of the nature of TREM1 ligand, engagement of TREM1 on neutrophils and monocytes results in initiation and amplification of inflammatory responses. It is likely that TREM1 recognizes a soluble protein or a cell-surface protein that is expressed ex novo or overexpressed as a result of inflammation and/or tissue damage (Ref.1).

TREM1 is expressed as a transmembrane receptor complex with the DAP12 chain subunit. The complex is stabilized through a unique electrostatic interaction between a negatively charged (-) amino acid in DAP12 and a positively charged (+) amino acid in TREM chains. After TREM crosslinking, the DAP12 ITAMs are phosphorylated, providing a docking site for protein tyrosine kinases: ZAP70 and SYK (Spleen Tyrosine Kinase) (Ref.3). SYK promotes the recruitment and tyrosine phosphorylation of adaptor complexes that contain Cbl, SOS and GRB2 (Growth Factor Receptor Binding Protein-2), which activate PI3K (Phosphatidylinositol 3-Kinase), PLC-Gamma (Phospholipase-C-Gamma) and the ERK (Extracellular-Signal-Regulated Kinase) pathways. These pathways induce Ca2+ mobilization, rearrangement of the actin cytoskeleton and activation of transcription factors, including Elk1, NFAT (Nuclear Factor of Activated T-Cells), c-Fos, c-Jun and NF-KappaB (Nuclear Factor-KappaB), which transcribe genes that encode proinflammatory cytokines, proinflammatory chemokines and cell-surface molecules (Ref.1). PI3K and ERK pathways that are triggered by TREM1 also promote mitochondrial integrity and cell survival by inactivating pro-apoptotic factors: BID (BH3-Interacting Domain Death agonist), BAD (BCL-2-Antagonist of cell Death) and BAX (BCL-2-Associated X-Protein) and the subsequent inhibition of release of CytoC (Cytochrome-C) from the mitochondria.

Cross-linking of TREM1 on neutrophils induces IL-8 (Interleukin-8) and MPO (Myeloperoxidase) secretion, while cross-linking on monocytes induces secretion of MCP1 (Monocyte Chemotactic Protein-1), and TNF (Tumor Necrosis Factor) in addition to IL-8. TREM1 engagement also induces upregulation of adhesion molecules e.g., ITGB1 (Integrin-Beta1); and costimulatory molecules e.g., TNFRSF5 (Tumor Necrosis Factor Receptor Superfamily, member 5). Thus, the expression and functional properties of TREM1 strongly advocate its role in acute inflammation (Ref.7). The TREM1 signaling cascade synergizes with the IL-1R (Interleukin-1 Receptor) and TLR (Toll-Like Receptor) signaling pathways. Engagement of TLR and IL-1R by respective ligands activate IRAK (interleukin-1-receptor-associated kinase), and TRAF6 (TNF-receptor-associated factor-6) activating signalling pathways that lead to subsequent activation of JNK (c-Jun Kinase-1), p38 and NF-KappaB (Nuclear Factor-KappaB). NF-KappaB induces the transcription and upregulation of expression of TREM1 itself. In addition, expression of TREM1 ligands might also be upregulated at the inflammatory site. The TREM1 signaling cascade also reinforces the production of inflammatory mediators that are initiated by TLRs and IL-1R signaling. In synergy with the TLR signaling, TREM1 activation in response to bacterial and fungal infections stimulates the release of IL-8 (Interleukin-8) and MPO (Myeloperoxidase) from neutrophils. In monocytes, this synergistic effect of TREM1 and TLR pathway leads to the production of a variety of inflammatory mediators like MCP1, MIP1Alpha (Macrophage Inflammatory Protein-1-Alpha), and IL-8, as well as TNF-Alpha and GM-CSF (Ref.7).

Sepsis and septic shock constitute a systemic response to infection that is characterized by a combined hyperinflammatory and immunosuppressive state, that result from a systemic response to infections, characterized by increased systemic levels of proinflammatory mediators e.g., TNF, IL-1Beta, HMGB1 (High Mobility Group Box-1) protein etc (Ref.8). The treatment of sepsis and septic shock, therefore, exploit the strategy of blocking or attenuating the proinflammatory cytokines, which can be brought about by modulation of TREM1 signaling. Similarly, TREM1 might be a therapeutic target in other inflammatory syndromes, such as acute lung injury, in which the accumulation of neutrophils leads to a marked release of proinflammatory cytokines, loss of epithelial and endothelial integrity and the development of interstitial pulmonary oedema. TREM1 is implicated as a potential therapeutic target in diseases characterized by an excessive inflammatory response to infections (Ref.5). Characterization of TREM1 natural ligands will further illuminate the mechanisms regulating innate responses against pathogens. Whatever may be the ligands, targeted activation or blockade of TREM1 may help maximize the efficacy of existing treatments for sepsis (Ref.1).