TREM1 Signaling

The triggering receptor expressed on myeloid cells 1(TREM1) belongs to the Immunoglobulin (Ig) family of cell surface receptors and is selectively expressed on blood neutrophils, monocytes and macrophages. TREM-1 lacks known signaling motifs in the cytoplasmic domain and thus activation by TREM1 is mediated by a transmembrane adaptor molecule DNAX-activating protein 12 (DAP12), leading to proinflammatory immune responses. The natural ligand for TREM1 is however, unknown.TREM1 activation triggers the Janus kinase 2 (JAK2), protein kinase B (PKB/AKT) and extracellular signal related kinase (ERK1/2) pathways leading to the phosphorylation of signal transducers of activation of transcription (STAT3, 5) and NF kappa B (NF-κB). These transcription factors upregulate the expression of genes involved in the inflammatory response. Stimulation of TREM by its ligand or toll like receptor (TLR) by lipopolysaccharide (LPS) can lead to an association of TREM1 and TLR. This association leads to the activation of interleukin-1 receptor-associated kinase 1(IRAK1), which in turn triggers NF-κB and the proinflammatory response. Engagement and activation of TREM-1 triggers expression and secretion of chemokines and cytokines like monocyte chemotactic protein 1(MCP-1) macrophage inflammatory protein-1alpha (MIP-1α), interleukins (IL-6,-8) and tumor necrosis factor (TNF).Many of these effects are potentiated by LPS. Cytokines like TNF and Granulocyte macrophage colony stimulating factor (GM-CSF) in turn upregulate the expression of TREM1 in an autocrine fashion. The synergy between TLR and TREM1 leads to neutrophil degranulation, phagocytosis and the respiratory burst in addition to the production of proinflammatory cytokines. TREM1 activation also results in the upregulation of cell surface proteins like CD11, CD29 and CD40, CD83 that are involved in cell adhesion and costimulation respectively, as well as phospholipase gamma (PLCγ) mediated Ca2+ release. Thus TREM1 activation is involved in diverse aspects of innate and adaptive immune response.In addition to TLRs, TREM1 also synergizes with a second major class of pattern recognition receptors -the NACHT-LRR receptors (NLR), which recognize intracellular microorganisms. The TREM-1/NLR synergism results in the production of proinflammatory cytokines like TNF, IL-1β, IL-6 and IL-18- the latter three via a caspase -1 dependent pathway. Thus TREM-1 acts to amplify signals from both major pathways of pattern recognition- extracellular TLR receptors and the intracellular NLR proteins.This pathway highlights the important components of TREM1 signaling.