TREM (triggering receptor expressed on myeloid cells) receptors are Ig-superfamily members that contain a single V-type Ig-like extracellular domain and a short cytoplasmic tail with no signaling motif.1,2 Three family members, TREM-1, -2, and -3, signal through the transmembrane adapter molecule DAP12.1-3 Their extracellular domains differ considerably, however, suggesting they each respond to different, unknown ligands.2 Two additional genes, TREM-4 and TREM-5, were recently identified.2 The TREM-4 sequence predicts an activating receptor, whereas the TREM-5 sequence is thought to represent a pseudogene.2
|Figure 1. Activation of TREM-1 by microbial components results in the acute inflammatory response characteristic of sepsis. Upon association with the signaling adapter molecule DAP12, TREM-1 mediates a host of responses, including the massive release of pro-inflammatory cytokines, MPO release, and increased expression of cell activation markers.|
TREM family members are involved in the regulation of inflammatory responses.1 Exposure to infectious agents results in up-regulation of TREM-1 on blood neutrophils and a subset of monocytes, primary mediators of the host innate immune response.1 TREM-1 activation triggers pro-inflammatory cytokine and chemokine release, increased surface expression of cell activation markers, release of myeloperoxidase (MPO), and increased neutrophil and monocyte survival at the site of inflammation, thus amplifying the acute inflammatory response1,4 (see Figure 1).
Sepsis, a dysregulated host response to microbial components, results in an excessive inflammatory response.4 Characterized by a massive release of pro-inflammatory cytokines, such as TNF-alpha and IL-1 beta, sepsis results in tissue damage, an uncontrollable decline in blood pressure, multiple organ failure, and ultimately, death.4-6 Several experiments performed by Bouchon et al.4 demonstrate that TREM-1 mediates the acute inflammatory response to microbial products that occurs in sepsis. First, human tissues infected with bacteria are infiltrated with neutrophils and monocytes that express high levels of TREM-1. Second, TREM-1 is only weakly expressed in patient samples with non-infective inflammatory disorders. Third, peritoneal neutrophils from microbial sepsis patients, and mice with LPS-induced shock, up-regulate TREM-1. Lastly, infected mice treated with mouse TREM-1/Fc produced significantly lower levels of TNF-alpha and IL-1 beta, and the mortality rate fell from 94% to 24%. This evidence demonstrates that TREM-1 is up-regulated by infectious agents, and that when blocked in a sepsis model, results in a reduced death rate. Thus, therapeutics which target TREMs, their ligands, or DAP12 signaling pathway members may prove beneficial in treating and preventing sepsis.