Uncovering the TREM-1-TLR connection

Abstract

EDITORIAL FOCUSUncovering the TREM-1-TLR connectionJulia Klesney-Tait, and Marco ColonnaJulia Klesney-Tait, and Marco ColonnaPublished Online:01 Dec 2007https://doi.org/10.1152/ajplung.00415.2007This is the final version - click for previous versionMoreSectionsPDF (113 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat 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.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-κB 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-κB-mediated responses that include TNF, IL-1, IL-12, IL-8, and MIP-1α 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-κB pathway [IκBα, 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. 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 PLCγ 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-κB 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-κB activation results in cytokine production, whereas TRAF3 and IRF3 contribute to type 1 INF production. Red arrows indicate potential TREM-1 TLR4 pathway interactions.Download figureDownload PowerPointREFERENCES1 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.Crossref | PubMed | ISI | Google Scholar2 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.Crossref | PubMed | ISI | Google Scholar3 Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. 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Klesney-Tait, Univ. of Iowa, Pulmonary, Critical Care, and Occupational Medicine, 200 Hawkins Drive, C34-12 GH, Iowa City, IA 52242-1081 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByA first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition20 July 2018 | British Journal of Clinical Pharmacology, Vol. 84, No. 10TREM-1 multimerization is essential for its activation on monocytes and neutrophils22 March 2018 | Cellular & Molecular Immunology, Vol. 164The identification, characterization, and function of two TREMs genes in Chinese Yangzhou goose ( Anas cygnoides )Developmental & Comparative Immunology, Vol. 73Efficacy of compound Qingre Granules on inflammatory markers in patients with fever of unknown origin: A randomized clinical trialEuropean Journal of Integrative Medicine, Vol. 10Knockdown of TREM-1 suppresses IL-1β-induced chondrocyte injury via inhibiting the NF-κB pathwayBiochemical and Biophysical Research Communications, Vol. 482, No. 4Effect of TREM-1 blockade and single nucleotide variants in experimental renal injury and kidney transplantation8 December 2016 | Scientific Reports, Vol. 6, No. 1Triggering receptor expressed on myeloid cells and 5’adenosine monophosphate-activated protein kinase in the inflammatory response: a potential therapeutic target13 June 2016 | Expert Review of Clinical Immunology, Vol. 12, No. 11Toll-like receptors, triggering receptor expressed on myeloid cells family members and receptor for advanced glycation end-products in allergic airway inflammation20 January 2016 | Expert Review of Respiratory Medicine, Vol. 10, No. 2TREM-1, an Inflammatory Modulator, is Expressed in Hepatocellular Carcinoma Cells and Significantly Promotes Tumor Progression3 December 2014 | Annals of Surgical Oncology, Vol. 22, No. 9The triggering receptor expressed on myeloid cells (TREM) in inflammatory bowel disease pathogenesis28 October 2014 | Journal of Translational Medicine, Vol. 12, No. 1Emerging roles for triggering receptor expressed on myeloid cells receptor family signaling in inflammatory diseases10 December 2013 | Expert Review of Clinical Immunology, Vol. 10, No. 2Inhibition of Innate Co-Receptor TREM-1 Signaling Reduces CD4 + T Cell Activation and Prolongs Cardiac Allograft Survival6 March 2013 | American Journal of Transplantation, Vol. 13, No. 5Silencing of triggering receptor expressed on myeloid cells-2 enhances the inflammatory responses of alveolar macrophages to lipopolysaccharide10 January 2013 | Molecular Medicine Reports, Vol. 7, No. 3Involvement of the TREM-1/DAP12 pathway in the innate immune responses to Porphyromonas gingivalisMolecular Immunology, Vol. 49, No. 1-2Nucleosides accelerate inflammatory osteolysis, acting as distinct innate immune activators20 July 2011 | Journal of Bone and Mineral Research, Vol. 26, No. 8TREM-1 and DAP12 expression in monocytes of patients with severe psychiatric disorders. EGR3, ATF3 and PU.1 as important transcription factorsBrain, Behavior, and Immunity, Vol. 25, No. 6Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) Modulates Immune Responses to Aspergillus fumigatus During Fungal Asthma in Mice19 May 2011 | Immunological Investigations, Vol. 40, No. 7-8Expression of TREM-1 is inhibited by PGD2 and PGJ2 in macrophagesExperimental Cell Research, Vol. 316, No. 19MYD88-dependent and -independent activation of TREM-1 via specific TLR ligands10 November 2009 | European Journal of Immunology, Vol. 40, No. 1Natural History of Innate Host Defense Peptides5 December 2009 | Probiotics and Antimicrobial Proteins, Vol. 1, No. 2Diagnostic Implications of Soluble Triggering Receptor Expressed on Myeloid Cells-1 in BAL Fluid of Patients With Pulmonary Infiltrates in the ICUChest, Vol. 135, No. 3Biomarkers: Diagnosis and Risk Assessment in SepsisClinics in Chest Medicine, Vol. 29, No. 4Mechanisms and Consequences of Dendritic Cell MigrationImmunity, Vol. 29, No. 3 More from this issue > Volume 293Issue 6December 2007Pages L1374-L1376 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00415.2007PubMed17934061History Published online 1 December 2007 Published in print 1 December 2007 Metrics