Triggering receptor expressed on myeloid cells‐1 (TREM‐1) amplifies the signals induced by the NACHT‐LRR (NLR) pattern recognition receptors

Triggering receptor expressed on myeloid cells‐1 (TREM‐1) is a member of a new family of myeloid receptors, encoded by a gene cluster linked to the MHC. Engagement of TREM‐1 stimulates intracellular signals, resulting in activation of phagocytosis, neutrophil degranulation, and amplification of cytokine production induced by TLRs. In the present study, a novel property following engagement of TREM‐1 is described, namely the amplification of cytokine production induced by the second major class of pattern recognition receptors, the NAIP, CIITA, HET‐E, TP‐1‐leucine‐rich repeat (NACHT‐LRR; NLR) receptors, which recognize intracellular microorganisms through sensing their muropeptide components of peptidoglycan. The TREM‐1/NLR synergism was observed for the production of TNF‐α, IL‐1β, and IL‐6, leading to an increase in cytokine production up to tenfold greater than the additive value of TREM‐1 or muropeptide stimulation alone. Several putative mechanisms are proposed to be involved in the synergism between NLRs and TREM‐1, including the increase in TREM‐1 expression by NLR ligands, and of the expression of nucleotide oligomerization domain‐2 receptor by TREM‐1 engagement. In contrast, although caspase‐1 modulates IL‐1β and IL‐6 production after stimulation with anti‐TREM‐1 antibodies or NLR ligands, it does not appear to be responsible for the synergism between these two pathways. These findings demonstrate that TREM‐1 acts on both major recognition pathways of bacterial structures: the extracellular TLR receptors, and the intracellular NLR molecules. This latter finding supports the concept that TREM‐1 provides optimal amplification of cytokine‐induced inflammation during the initiation of host defense.