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Published online before print August 29, 2006

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(Journal of Leukocyte Biology. 2006;80:1454-1461.)
© 2006 by Society for Leukocyte Biology

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

Mihai G. Netea^*,,1, Tania Azam^*, Gerben Ferwerda, Stephen E. Girardin, Soo-Hyun Kim^*,2 and Charles A. Dinarello^*

^* Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA;
Nijmegen University Center for Infectious Diseases, Nÿmegen, The Netherlands; and
Unité Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, France

¹ Correspondence: Division of Infectious Diseases, B168 University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA. E-mail: M.Netea{at}aig.umcn.nl

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-, 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.

Key Words: NOD2 • cytokines • caspase-1

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