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-alpha, IL-1beta, 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-1beta 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.
Netea
Mihai G
MG
Division of Infectious Diseases, B168 University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA. M.Netea@aig.umcn.nl
Azam
Tania
T
Ferwerda
Gerben
G
Girardin
Stephen E
SE
Kim
Soo-Hyun
SH
Dinarello
Charles A
CA
D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
D016207:Cytokines; D008562:Membrane Glycoproteins; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan; D011971:Receptors, Immunologic; D051192:Receptors, Pattern Recognition; C408842:TREM1 protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D020170:Caspase 1