Exploring Toll-like Receptor-4 Associated Single Nucleotide Polymorphisms and Susceptibility to Microbial Infections

Toll-like receptor 4 (TLR4) is a key factor in the innate immune recognition of lipopolysaccharide (LPS) from Gram-negative bacteria. Previous studies from our group identified differences in the expression profile of TLR4 and genes affected by the TLR4 signaling pathway among pigs that shed varying levels of Salmonella, a Gram-negative bacterium. Therefore, genetic variation in this gene may be involved with the host's immune response to bacterial infections. The current study screened for single nucleotide polymorphisms (SNPs) in the TLR4 gene and tested their association with Salmonella fecal shedding. Pigs (n = 117) were intranasally challenged at 7 weeks of age with 1 × 10(9) CFU of S. Typhimurium χ4232 and were classified as low or persistent Salmonella shedders based on the levels of Salmonella being excreted in fecal material. Salmonella fecal shedding was determined by quantitative bacteriology on days 2, 7, 14, and 20/21 post exposure, and the cumulative levels of Salmonella were calculated to identify the low (n = 20) and persistent (n = 20) Salmonella shedder pigs. From those 40 animals, the TLR4 region was sequenced, and 18 single nucleotide polymorphisms (SNPs) in TLR4 were identified. Twelve SNPs have been previously described and six are novel SNPs of which five are in the 5' untranslated region and one is in intron 2. Single marker association test identified 13 SNPs associated with the qualitative trait of Salmonella fecal shedding, and seven of those SNPs were also associated with a quantitative measurement of fecal shedding (P < 0.05). Using a stepwise regression process, a haplotype composed of SNPs rs80787918 and rs80907449 (P ≤ 4.0 × 10(-3)) spanning a region of 4.9 Kb was identified, thereby providing additional information of the influence of those SNPs on Salmonella fecal shedding in pigs.

Toll-like receptor 4 (TLR4) is a key factor in the innate immune recognition of lipopolysaccharide (LPS) from Gram-negative bacteria. Previous studies from our group identified differences in the expression profile of TLR4 and genes affected by the TLR4 signaling pathway among pigs that shed varying levels of Salmonella, a Gram-negative bacterium. Therefore, genetic variation in this gene may be involved with the host’s immune response to bacterial infections. The current study screened for single nucleotide polymorphisms (SNPs) in the TLR4 gene and tested their association with Salmonella fecal shedding. Pigs (n = 117) were intranasally challenged at 7 weeks of age with 1 × 109 CFU of S. Typhimurium χ4232 and were classified as low or persistent Salmonella shedders based on the levels of Salmonella being excreted in fecal material. Salmonella fecal shedding was determined by quantitative bacteriology on days 2, 7, 14, and 20/21 post exposure, and the cumulative levels of Salmonella were calculated to identify the low (n = 20) and persistent (n = 20) Salmonella shedder pigs. From those 40 animals, the TLR4 region was sequenced, and 18 single nucleotide polymorphisms (SNPs) in TLR4 were identified. Twelve SNPs have been previously described and six are novel SNPs of which five are in the 5′ untranslated region and one is in intron 2. Single marker association test identified 13 SNPs associated with the qualitative trait of Salmonella fecal shedding, and seven of those SNPs were also associated with a quantitative measurement of fecal shedding (P < 0.05). Using a stepwise regression process, a haplotype composed of SNPs rs80787918 and rs80907449 (P ≤ 4.0 × 10−3) spanning a region of 4.9 Kb was identified, thereby providing additional information of the influence of those SNPs on Salmonella fecal shedding in pigs.Electronic supplementary materialThe online version of this article (doi:10.1007/s13353-014-0199-8) contains supplementary material, which is available to authorized users.

Toll-like receptor 4 gene polymorphisms and susceptibility to juvenile idiopathic arthritis

Toll-like receptor 4 (TLR4) appears to play an important role in the development and progression of hepatocellular carcinoma (HCC), but it is unclear whether single-nucleotide polymorphisms (SNPs) in the TLR4 gene influence HCC. In this study, we investigated the effects of TLR4 SNPs on HepG2 cell survival and proliferation, migration, and invasion. Plasmids carrying wild-type or mutant versions of the TLR4 gene (A896G and/or C1196T) were stably transfected into HepG2 cells, and cell viability and proliferation were analyzed using the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays, whereas apoptosis was assessed using flow cytometry. Migration and invasion were measured in a transwell chamber assay, and expression of inflammatory cytokines and downstream effectors was examined using real-time PCR and western blotting. Specific inhibitors of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), or phosphatidylinositol 3-kinase (PI3K) were added to the HepG2 cultures to explore the potential role of each pathway in TLR4 signaling. TLR4 SNPs did not affect expression levels in transfected cells. Compared with wild-type TLR4, mutant TLR4 was associated with lower cell proliferation, migration, invasion, and apoptotic threshold. In addition, the mutations were associated with significantly lower expression of nuclear factor κB (NF-κB), IL-6, and TGF-β1, even after stimulation with lipopolysaccharide. The expression of p-Akt was similar in the presence of wild-type or mutant TLR4. The 896G and 1196T SNPs in the TLR4 gene are associated with reduced TLR4-mediated signaling and, therefore, with lower survival, proliferation, and metastasis in HepG2 cells.

Aim:Toll-like receptor 2 (TLR2) and TLR4 genes play critical roles in host recognition of Mycobacterium bovis infection and initiation of innate and adaptive immune response. The present study was aimed at exploring the association of seven single nucleotide polymorphisms (SNPs) in TLR2 and TLR4 genes with susceptibility/resistance against bovine tuberculosis (bTB) infection in cattle.Materials and Methods:A case-control resource population of 35 positive and 45 negative animals was developed after screening with single intradermal tuberculin test for bTB. Resource population was screened for SNPs in TLR2 and TLR4 genes using polymerase chain reaction-restriction fragment length polymorphism. The PROC LOGISTIC procedure of SAS 9.3 was used to find an association of allelic and genotypic frequencies with bTB.Results:In TLR2 gene, two of SNPs under study (rs55617172 and rs68268253) revealed polymorphism while in the case of TLR4 gene all four SNPs under investigation (rs8193041, rs207836014, rs8193060, and rs8193069) were found to be polymorphic in case-control population. SNP locus rs55617172 in TLR2 gene was found significantly (p<0.01) associated with susceptibility/resistance to TB in cattle.Conclusion:These findings indicate the presence of SNPs in TLR2 and TLR4 genes in our resource population. Upon validation in independent, large resource population and following biological characterization, SNP rs55617172 can be incorporated in marker panel for selection of animals with greater resistance to bTB.

Background: Several lines of evidence support the roles of inflammation and infection in prostate cancer development and progression. Common genetic variants involved in pathways of inflammation and immune response may be important for prostate cancer. The Toll-like receptor 4 (TLR4) is a cell surface receptor that mediates immune response. TLR4 recognizes LPS (endotoxin) on gram-negative bacteria, resulting in NF-kappaB and cytokine production as well as inducing interferon expression. In vitro studies suggest that stimulation of TLR4 with LPS promotes prostate tumor growth. Yet, single nucleotide polymorphisms (SNPs) on TLR4 have been inconsistently associated with prostate cancer risk, and only one published study has looked at survival as an endpoint. Methods: In a large nested case control study of prostate cancer in the Physicians’ Health Study (1982-2004), 10 SNPs were selected and genotyped to capture common variation within the TLR4 gene as well as 5 kilobases up and downstream. SNPs that were not directly tagged were imputed using the observed genotypes, the HapMap CEPH data, and the MACH imputation program. Unconditional logistic regression controlling for matching factors (age at randomization, smoking status and duration of follow-up) assessed the association of these SNPs and prostate cancer risk (odds ratios (OR) and 95% confidence intervals (CI)), as well as risk defined by advanced cancer stage (T3/T4, T0-T4/M1, fatal disease) or high Gleason grade (&amp;gt;=7). Time to event analysis using Cox-proportional hazards regression assessed risk of progression to metastases and death among prostate cancer cases through March 2009. Results: The case-control analysis included 1286 prostate cancer cases and 1267 controls; there were 237 advanced stage and 560 high grade cases. An additional 45 men who were originally controls developed prostate cancer and were also included in the case-only survival analysis. During a median of 10.6 years of follow-up, 183 men died of prostate cancer or developed distant metastases. No significant associations between the TLR4 SNPs were found for total prostate cancer risk, including SNPs for which an association was reported in other published studies: rs2149356 (OR:0.89, CI: 0.66, 1.18); rs2737191 (OR: 1.01, CI:0.75, 1.37); rs10759932 (OR: 1.08, CI: 0.89, 1.3); rs11536889 (OR: 0.99, CI: 0.83, 1.19). There were no significant associations for risk of advanced stage or high grade cancers, or progression to metastases or death. Conclusions: Results from this prospective nested case-control study, with a large number of aggressive cancers and comprehensive SNP selection on TLR4, suggest that genetic variation across TLR4 is not associated with prostate cancer risk or progression. The results do not replicate the findings of previous studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 920.

Toll-like Receptor 9 Triggers an Innate Immune Response to Helper-dependent Adenoviral Vectors

Respiratory syncytial virus is a leading cause of lower respiratory tract infection in infants. Disease severity has been linked to host immune responses and polymorphisms in genes associated with innate immunity. A large-scale genetics study of single nucleotide polymorphisms (SNPs) in children in the Netherlands identified SNPs in the vitamin D receptor (VDR) and JUN genes which have a strong association with an increased risk of developing bronchiolitis following the first respiratory syncytial virus (RSV) infection. The Toll-like receptor 4 (TLR4) gene has two SNPs which have been associated previously with RSV disease severity in various populations. The aim of this study was to determine if these SNPs may be associated with RSV disease in African children in South Africa. RSV patient (n = 296) and control (n = 113) groups were established (median ages: 3 and 3.5 months) and DNA extracted from the collected specimens. Real-time polymerase chain reaction using hydrolysis probes was used to screen for SNPs in the VDR (Thr1Meth; rs10735810), TLR4 (Asp299Gly; rs4986790 and Thr399Ile; rs4986791) and JUN (c.750G/A; rs11688) genes. Carriers of the VDR (Thr1Meth) SNP minor T allele were more prone to RSV disease than individuals in the control group. The TLR4 (Asp299Gly), TLR4 (Thr399Ile), and JUN (c.750G/A) SNPs showed no significant association with RSV disease. It is concluded that children carrying the minor T allele of the VDR (Thr1Meth) SNP may be predisposed to RSV disease, as this SNP was identified as a risk factor for severe RSV disease in South African children, confirming the findings in the Netherlands.

BackgroundStevens-Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, often including the ocular surface, and toxic epidermal necrolysis (TEN) occurs with its progression. Although SJS/TEN is thought to be initiated by certain types of medication coupled with possible infection. In the present study we examined the multiplicative interaction(s) between HLA-A*0206 and 7 Toll-like receptor 3 (TLR3) Single-nucleotide polymorphisms (SNPs) in patients with SJS/TEN.Principal FindingsWe analyzed the genotypes for HLA-A and 7 TLR3 SNPs in 110 Japanese SJS/TEN patients with severe ocular complications and 206 healthy volunteers to examine the interactions between the two loci. We found that HLA-A*0206 exhibited a high odds ratio for SJS/TEN (carrier frequency: OR = 5.1; gene frequency: OR = 4.0) and that there was a strong association with TLR3 rs.5743312T/T SNP (OR = 7.4), TLR3 rs.3775296T/T SNP (OR = 5.8), TLR3 rs.6822014G/G SNP (OR = 4.8), TLR3 rs.3775290A/A SNP (OR = 2.9), TLR3 rs.7668666A/A SNP (OR = 2.7), TLR3 rs.4861699G/G SNP (OR = 2.3), and TLR3 rs.11732384G/G SNP (OR = 1.9). There was strong linkage disequilibrium (LD) between rs.3775296 and rs.5743312 and between rs.7668666 and rs.3775290. The results of interaction analysis showed that the pair, HLA-A*0206 and TLR3 SNP rs3775296T/T, which exhibited strong LD with TLR3 rs.5743312, exerted more than additive effects (OR = 47.7). The other pairs, HLA-A*0206 and TLR3 rs.3775290A/A SNP (OR = 11.4) which was in strong LD with TLR3 rs7668666A/A SNP, and TLR3 rs4861699G/G SNP (OR = 7.6) revealed additive effects. Moreover, the combination HLA-A*0206 and TLR3 rs3775296T/T was stronger than the TLR3 rs6822014G/G and TLR3 rs3775290A/A pair, which reflected the interactions within the TLR3 gene alone.SignificanceBy interaction analysis, HLA-A*0206 and TLR3 SNP rs3775296T/T, which were in strong LD with TLR3 SNP rs5743312T/T, manifested more than additive effects that were stronger than the interactions within the TLR3 gene alone. Therefore, multiplicative interactions of HLA-A and TLR3 gene might be required for the onset of SJS/TEN with ocular complications.

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 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. Nature 410: 1103–1107, 2001.Crossref | PubMed | ISI | Google Scholar4 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.Crossref | PubMed | ISI | Google Scholar5 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.Crossref | PubMed | ISI | Google Scholar6 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 | PubMed | ISI | Google Scholar7 Haselmayer P, Grosse-Hovest L, von Landenberg P, Schild H, Radsak MP. TREM-1 ligand expression on platelets enhances neutrophil activation. 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Sci STKE 2005: cm7, 2005.Google Scholar18 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 | PubMed | ISI | Google ScholarAUTHOR NOTESAddress 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: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited 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

Association of single-nucleotide polymorphisms in toll-like receptor 5 gene with rheumatic heart disease in Chinese Han population

The suggestion that there is a connection between chronic intraprostatic inflammation and prostate cancer was declared some years ago. As Toll-like receptors (TLRs) are the key players in the processes of chronic intraprostatic inflammation, there is a hypothesis that TLR gene polymorphisms may be associated with prostate cancer risk. Although a number of comprehensive studies have been conducted on large samples in various countries, reliable connections between these single nucleotide polymorphisms and prostate cancer risk, stage, grade, aggressiveness, ability to metastasize, and mortality have not been detected. Results have also varied slightly in different populations. The data obtained regarding the absence of connection between the polymorphisms of the genes encoding interleukin-1 receptor-associated kinases (IRAK1 and IRAK4) and prostate cancer risk might indicate a lack of association between inherited variation in the TLR signaling pathway and prostate cancer risk. It is possible to consider that polymorphisms of genes encoding TLRs and proteins of the TLR pathway also do not play a major role in the etiology and pathogenesis of prostate cancer. Feasibly, it would be better to focus research on associations between TLR single nucleotide polymorphisms and cancer risk in other infection-related cancer types.

Bacterial meningitis (BM) is a severe infection mainly caused by Streptococcus pneumoniae and Neisseria meningitidis (NM). However, genetically determined susceptibility to develop severe infections by these microorganisms is variable between individuals. Toll-like receptor 9 (TLR9) recognizes bacterial DNA leading to intracellular inflammatory signaling. Single nucleotide polymorphisms (SNPs) within the TLR9 gene are associated with susceptibility to several diseases, no such association with meningitis has been described. We studied the role of TLR9 SNPs in host defense against BM. Two TLR9 SNPs and 4 TLR9 haplotypes were determined in 472 survivors of BM and compared to 392 healthy controls. Carriage of the TLR9+2848-A mutant was significantly decreased in meningococcal meningitis (MM) patients compared with controls (p: .0098, odds ratio [OR]: .6, 95% confidence interval [CI]: .4-.9). TLR9 haplotype I was associated with an increased susceptibility to MM (p: .0237, OR 1.3, 95% CI: 1.0-1.5). In silico analysis shows a very strong immunoinhibitory potential for DNA of NM upon recognition by TLR9 (CpG index of -106.8). We report an association of TLR9 SNPs with susceptibility to BM, specifically MM indicating a protective effect for the TLR9+2848-A allele. We hypothesize that the TLR9+2848-A mutant results in an up-regulation of TLR9 induced immune response compensating the strong inhibitory potential of NM CpG DNA.

Toll-like receptor 9 (TLR9) is an important component of the innate immune system and have been associated with several autoimmune diseases, such as Systemic Lupus Erythematosus (SLE). The aim of this study was to investigate polymorphisms in TLR9 gene in a Brazilian SLE patients group and their association with clinical manifestation, particularly Jaccoud's arthropathy (JA). We analyzed DNA samples from 204 SLE patients, having a subgroup of them presenting JA (n=24). A control group (n=133) from the same city was also included. TLR9 single nucleotide polymorphisms (SNPs) (-1237 C>T and +2848 G>A) were identified by sequencing analysis. The TLR9 gene genotype frequency was similar both in SLE patients and the control group. In the whole SLE population, an association between the homozygosis of allele C at position -1237 with psychosis and anemia (p < 0.01) was found. Likewise, the homozygosis of allele G at position +2848 was associated with a discoid rash (p < 0.05). There was no association between JA and TLR9 polymorphisms. These data show that TLR9 polymorphisms do not seem to be a predisposing factor for SLE in the Brazilian population, and that SNPs are not associated with JA.

Single-nucleotide polymorphisms in Toll-like receptor genes are associated with the prognosis of gastric cancer and are not associated with Helicobacter pylori infection