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Am J Physiol Lung Cell Mol Physiol 293: L1374-L1376, 2007. First published October 12, 2007; doi:10.1152/ajplung.00415.2007
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EDITORIAL FOCUS

Uncovering the TREM-1-TLR connection

Julia Klesney-Tait1 and Marco Colonna2

1University of Iowa Hospitals and Clinics, Pulmonary, Occupational Medicine, and Critical Care, Iowa City, Iowa; and 2Washington University School of Medicine, Immunology and Pathology, St. Louis, Missouri

THE INNATE IMMUNE SYSTEM HAS several large genetically encoded receptor families that interact during the detection and elimination of pathogens. The Toll-like receptor (TLR) family recognizes a diverse group of evolutionarily conserved molecules including lipopolysaccharide (LPS), peptidoglycan, and nucleic acids (16). Engagement of these receptors results in proinflammatory signaling. Another family of innate immune receptors, triggering receptors expressed on myeloid cells (TREM), is capable of altering the downstream signaling potential of the TLR molecules. The TREM family contains both inhibitory and activating receptors that act to fine-tune the inflammatory response mediated by TLR (9). The novel report by Ornatowska and colleagues (15), which appears in this issue of AJP-Lung, sheds light on the intersection between these two families and how molecular cross talk may be functioning to tailor inflammatory responses.

TREM-1 is an activating receptor expressed on neutrophils and monocyte macrophages. The TREM-1 molecule consists of an ectodomain, a transmembrane region, and a short cytoplasmic tail lacking any signaling motifs. The transmembrane domain of TREM-1 has a positively charged residue that mediates the formation of a complex with the signaling adaptor DAP12. DAP12 contains an immunoreceptor tyrosine-based activation motif that upon phosphorylation mediates downstream signaling molecule recruitment (Fig. 1) (10, 11, 12, 17). Studies have shown that TREM-1 is upregulated in infection in vivo and following TLR engagement in vitro (2, 14). Cotriggering of TREM-1 and TLR4 results in a 25-fold synergistic increase in TLR4-mediated proinflammatory cytokine and chemokine secretion (1, 2). More recently, colocalization of TREM-1 and TLR4 in lipid rafts was demonstrated following either LPS stimulation or TREM-1 ligation in neutrophils (4). These data suggest that following microbial challenges in vivo, the two pathways may act synergistically to trigger an exuberant immune response. While epithelial cells, endothelial cells, and other cell types express TLR4, coexpression of TLR4 and TREM-1 is limited to macrophage and neutrophils providing these immune cells with a selective advantage in terms of shaping a local inflammatory response through more effective inflammatory signaling.


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  		Fig. 1. Simplified overview of triggering receptors expressed on myeloid cells-1 (TREM-1)/DAP12 and Toll-like receptor 4 (TLR4) signaling events. TREM-1 ligand binding leads to Src kinase-mediated DAP12 phosphorylation and recruitment of spleen tyrosine kinase (SYK). Subsequently scaffolding molecules LAT (linker for activation of T cells) and NTAL (non-T-cell activation linker) are phosphorylated, and phosphatidylinositol 3-kinase (PI3K) is activated. Ultimately, AKT, CBL (Casitas B-lineage lymphoma), ERK (extracellular signal-regulated kinase), and PLC{gamma} are recruited. These events lead to calcium flux, actin polymerization, and cytokine secretion. TLR4 engagement results in initiation of the MyD88 and TIRAP or TRIF and TRAM pathways. The MyD88-dependent pathway leads to the recruitment of IL-1R-associated kinases (IRAKs), ultimately resulting in mitogen-activated protein kinase activation, NF-{kappa}B activation, and inflammatory cytokine production. TRIF-dependent (MyD88-independent) signaling requires TRIF and TRAM recruitment. This pathway results in type 1 interferon (INF) production as well as inflammatory cytokine production. Receptor-interacting protein 1 (RIP) recruitment and subsequent NF-{kappa}B activation results in cytokine production, whereas TRAF3 and IRF3 contribute to type 1 INF production. Red arrows indicate potential TREM-1 TLR4 pathway interactions.

 
In animal studies of LPS-induced endotoxemia, the impact of reducing TREM-1 signaling by administration of soluble forms of the TREM-1 molecule, via small molecule blocker (LP17), and silencing RNA was examined (3, 5, 6). All three of these approaches have shown that decreased TREM-1 signaling results in decreased systemic cytokine production and improved survival in these models of endotoxemia. However, in murine fecal peritonitis models, conflicting data on the effect of TREM-1 blockade have been reported. TREM-1 blockade with soluble TREM-1 or the small molecule inhibitor resulted in improved survival, whereas small interfering RNA (siRNA) blockade of TREM-1 resulted in decreased survival. It is worth noting that for these studies, because TREM-1 ligand has remained elusive, blockade of TREM signaling was achieved by surrogate means. Whether these opposing results represent the different experimental conditions or variable levels of TREM-1 blockade is unclear, and identification of TREM-1 ligands remains a critical missing component to understanding the role of this molecule in sepsis.

In their recent article, Ornatowska et al. (15) expand our understanding of the potential mechanism of TREM-1 modulation on TLR4 signaling. Using siRNA silencing of TREM-1 and pathway-specific microarray analysis, they show that TREM-1 silencing in macrophage results in decreased transcription of key proteins in the TLR4 signaling pathway. This downregulation of adaptor proteins during TREM-1 silencing suggests that TREM-1 may be impacting cytokine and chemokine production by increasing the availability of downstream signaling molecules in the setting of acute inflammation.

When TLR4 binds, MD2/LPS Toll/IL-1R homology (TIR) domain containing adaptor molecules are recruited. These molecules can trigger two main signaling pathways: MyD88-dependent and TRIF-dependent (MyD88-independent) pathways. Signal transduction through both of these pathways will result in activation of NF-{kappa}B and mitogen-activated protein kinase cascades leading to inflammatory cytokine production. However, only TRIF-dependent pathways result in interferon (INF) and INF-inducible gene expression (16). Because adaptor recruitment dictates downstream cytokine expression, an understanding of the molecular events that control adaptor molecule recruitment is an area of intense investigation. Macrophage can utilize MyD88, TRIF, TRAM, or MAL/TIRAP adaptors following TLR4 ligation. TLR4 recruitment of TRIF results in INF production, whereas MyD88 recruitment leads to NF-{kappa}B-mediated responses that include TNF, IL-1, IL-12, IL-8, and MIP-1{alpha} production. Clearly, alterations in either selective adaptor recruitment or adaptor availability allow the immune system to tailor the output of the response following TLR ligation.

TREM-1 silencing did not alter TRIF-mediated expression of INF indicating that TREM-1 may not play a significant role in amplifying this TLR signaling pathway. However, the impact of TREM-1 silencing on MyD88, CD14, and other downstream signaling molecules could be the explanation for the decreased proinflammatory signaling observed both in vitro and in vivo following TREM-1 silencing. These authors noted significant decreases in MyD88 and CD14 transcripts as well as decreases in downstream molecules in the NF-{kappa}B pathway [I{kappa}B{alpha}, precursor to p50 (p100), CEBP-B] following LPS stimulation in the setting of TREM-1 silencing. These data provide an explanation for how TREM-1 is able to amplify the output of the TLR4 response. It would be interesting to examine whether TREM-1 silencing in the in vivo models results in decreased levels of these signaling molecules as is noted in these in vitro studies.

Another intriguing question is whether different TREM-1 ligands can potentially cause alterations in TLR4 recruitment of adaptor proteins that ultimately control whether MYD88-dependent or -independent pathways are favored. Indeed, it seems that TREM-1 molecules, like many other innate immune receptors, may have the ability to bind multiple ligands. TREM-1 binding to platelets, serum, and viruses has been described, although no ligands have been identified (7, 13, 18). Recent structural data from TLR4/MD2/LPS cocrystals reveal that TLR4's interaction with LPS is not a direct interaction but is in fact mediated via MD2 (8). Whether TREM-1 ligands are similar multimeric complexes awaits discovery.

As functional genomic approaches enable us to identify overlapping signal pathways, the relationship between TREM-1 and TLR downstream signaling molecules will provide a more complete picture of the pathways involved in inflammation and identify potential therapeutic targets to alter these responses.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Klesney-Tait, Univ. of Iowa, Pulmonary, Critical Care, and Occupational Medicine, 200 Hawkins Drive, C34-12 GH, Iowa City, IA 52242-1081 (e-mail: julia-klesney-tait{at}uiowa.edu)


   REFERENCES
TOP
 REFERENCES
 

  1. Bleharski JR, Kiessler V, Buonsanti C, Sieling PA, Stenger S, Colonna M, Modlin RL. A role for triggering receptor expressed on myeloid cells-1 in host defense during the early-induced and adaptive phases of the immune response. J Immunol 170: 3812–3818, 2003.[Abstract/Free Full Text]
  2. Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol 164: 4991–4995, 2000.[Abstract/Free Full Text]
  3. Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 410: 1103–1107, 2001.[CrossRef][Medline]
  4. Fortin CF, Lesur O, Fulop T Jr. Effects of TREM-1 activation in human neutrophils: activation of signaling pathways, recruitment into lipid rafts and association with TLR4. Int Immunol 19: 41–50, 2007.[Abstract/Free Full Text]
  5. Gibot S, Kolopp-Sarda MN, Bene MC, Bollaert PE, Lozniewski A, Mory F, Levy B, Faure GC. A soluble form of the triggering receptor expressed on myeloid cells-1 modulates the inflammatory response in murine sepsis. J Exp Med 200: 1419–1426, 2004.[Abstract/Free Full Text]
  6. Gibot S, Massin F, Marcou M, Taylor V, Stidwill R, Wilson P, Singer M, Bellingan G. TREM-1 promotes survival during septic shock in mice. Eur J Immunol 37: 456–466, 2007.[CrossRef][Web of Science][Medline]
  7. Haselmayer P, Grosse-Hovest L, von Landenberg P, Schild H, Radsak MP. TREM-1 ligand expression on platelets enhances neutrophil activation. Blood 110: 1029–1035, 2007.[Abstract/Free Full Text]
  8. Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, Enkhbayar P, Matsushima N, Lee H, Yoo OJ, Lee JO. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130: 906–917, 2007.[CrossRef][Web of Science][Medline]
  9. Klesney-Tait J, Turnbull IR, Colonna M. The TREM receptor family and signal integration. Nat Immunol 7: 1266–1273, 2006.[CrossRef][Web of Science][Medline]
  10. Lanier LL. Natural killer cell receptor signaling. Curr Opin Immunol 15: 308–314, 2003.[CrossRef][Web of Science][Medline]
  11. MacFarlane AW IV, Campbell KS. Signal transduction in natural killer cells. Curr Top Microbiol Immunol 298: 23–57, 2006.[Web of Science][Medline]
  12. McVicar DW, Burshtyn DN. Intracellular signaling by the killer immunoglobulin-like receptors and Ly49. Sci STKE 2001: RE1, 2001.[Medline]
  13. Mohamadzadeh M, Coberley SS, Olinger GG, Kalina WV, Ruthel G, Fuller CL, Swenson DL, Pratt WD, Kuhns DB, Schmaljohn AL. Activation of triggering receptor expressed on myeloid cells-1 on human neutrophils by marburg and ebola viruses. J Virol 80: 7235–7244, 2006.[Abstract/Free Full Text]
  14. Nathan C, Ding A. TREM-1: a new regulator of innate immunity in sepsis syndrome. Nat Med 7: 530–532, 2001.[CrossRef][Web of Science][Medline]
  15. Ornatowska M, Azim AC, Wang X, Christman JW, Xiao L, Joo M, Sadikot RT. Functional genomics of silencing TREM-1 on TLR4 signaling in macrophages. Am J Physiol Lung Cell Mol Physiol (September 28, 2007). doi:10.1152/ajplung.00140.2007.
  16. Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol 17: 1–14, 2005.[Abstract/Free Full Text]
  17. Vely F, Vivier E. Natural killer cell receptor signaling pathway in mammals. Sci STKE 2005: cm7, 2005.
  18. Wong-Baeza I, Gonzalez-Roldan N, Ferat-Osorio E, Esquivel-Callejas N, Aduna-Vicente R, Arriaga-Pizano L, Astudillo-de la Vega H, Villasis-Keever MA, Torres-Gonzalez R, Estrada-Garcia I, Lopez-Macias C, Isibasi A. Triggering receptor expressed on myeloid cells (TREM-1) is regulated post-transcriptionally and its ligand is present in the sera of some septic patients. Clin Exp Immunol 145: 448–455, 2006.[CrossRef][Web of Science][Medline]




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