Variation matters: TLR structure and species-specific pathogen recognition

Werling, Dirk; Jann, O.; Offord, Victoria; Glass, Elizabeth J.; Coffey, Tracey J.

doi:10.1016/j.it.2008.12.001

Cited by 233 publications

(184 citation statements)

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“…Of all the TLRs, TLR7, TLR8, and TLR9 (TLR7-9) share a more close phylogenetic relationship and thus comprise a subfamily. Additionally, in contrast to other TLRs, these three TLRs have a unique undefined region between LRR14 and LRR15 that may play a role in ligand binding (11)(12)(13)(14).…”

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confidence: 99%

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

Lai

Yeh

et al. 2015

The Journal of Immunology

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Activation of TLR7–9 has been linked to the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Thus, therapeutic applications of antagonists of these TLRs for such disorders are being investigated. Bortezomib (Velcade) is a proteasome inhibitor known to suppress activation of these TLRs. To identify novel TLR7–9 inhibitors, we searched the Gene Expression Omnibus database for gene expression profiles of bortezomib-treated cells. These profiles were then used to screen the Connectivity Map database for chemical compounds with similar functions as bortezomib. A natural antibiotic, thiostrepton, was identified for study. Similar to bortezomib, thiostrepton effectively inhibits TLR7–9 activation in cell-based assays and in dendritic cells. In contrast to bortezomib, thiostrepton does not inhibit NF-κB activation induced by TNF-α, IL-1, and other TLRs, and it is less cytotoxic to dendritic cells. Thiostrepton inhibits TLR9 localization in endosomes for activation via two mechanisms, which distinguish it from currently used TLR7–9 inhibitors. One mechanism is similar to the proteasome inhibitory function of bortezomib, whereas the other is through inhibition of endosomal acidification. Accordingly, in different animal models, thiostrepton attenuated LL37- and imiquimod-induced psoriasis-like inflammation. These results indicated that thiostrepton is a novel TLR7–9 inhibitor, and compared with bortezomib, its inhibitory effect is more specific to these TLRs, suggesting the potential therapeutic applications of thiostrepton on immunologic disorders elicited by inappropriate activation of TLR7–9.

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confidence: 99%

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

Lai

Yeh

et al. 2015

The Journal of Immunology

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“…TLR-mediated effects are increasingly recognized as not only being species-, tissue-, and cell-specific, but also condition-and tumor dependent [3,11,[50][51][52][53][54][55]. This heterogeneity is evident from the contradictory findings from studies that investigated TLR2 signaling in various tumor models [3,11,53,56].…”

Section: Discussionmentioning

confidence: 99%

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

et al. 2015

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Reports of spontaneous acute lymphoblastic leukemia (ALL) remissions following severe bacterial infections suggest that bacterial components may trigger elimination of ALL. To date, TLR2, which recognizes a broad range of bacterial pathogens through TLR1 or TLR6 heterodimerization, has not been fully evaluated for direct effects on ALL. Studies investigating TLR2 signaling in other tumor cell types utilizing single ligands have yielded contradictory results, and comparative, heterodimer-specific analyses of TLR2 stimulation are lacking. In this study, we report that two well-characterized heterodimer-specific TLR2 ligands, Pam 3 CSK 4 (TLR2/1), and Pam 2 CSK 4 (TLR2/6), induce ALL cell lines and primary ALL samples to upregulate CD40 expression. However, only Pam 3 CSK 4 triggers Caspase-8-mediated apoptosis and sensitizes cells to vincristine-mediated cytotoxicity. Consistent with this result, stimulation of ALL cells through TLR2/1 or TLR2/6 activates Mal, p38 and the NF-κB and PI3K signaling pathways with divergent kinetics that may underlie their distinct downstream effects. Our results reveal a novel branching in downstream responses to heterodimer-specific TLR2 stimulation in ALL cells and emphasize the need for comparative studies to determine differential biological effects observed in specific tumor cells. Based on our results, TLR2/1 ligand Pam 3 CSK 4 possesses potential for generating anti-ALL activity through its direct effects on leukemic blasts.Keywords: CD40 r Caspase-8-mediated apoptotic cell death r Heterodimer-specific TLR2 stimulation r Pediatric acute lymphoblastic leukemia r Signaling kinetics Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIt is now widely accepted that tumor remissions induced by the proinflammatory activity of Coley's toxin, which contains various bacterial components, is mediated by the engagement of TollCorrespondence: Dr. Kirk R. Schultz e-mail: kschultz@mail.ubc.ca like receptors (TLRs) on immune cells [1][2][3][4][5]. TLRs are a family of germline-encoded pattern recognition receptors that induce innate and adaptive immune responses after binding pathogenand damage-associated molecular patterns [6][7][8][9][10]. In recent years, many studies have demonstrated that purified TLR ligands exert * These authors contributed equally to this work as senior authors.www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1980-1990 Immunomodulation 1981 potent anti-cancer effects against various types of established tumors in both mice and humans [2,5]. However, while some TLR ligands are currently in clinical trials [11,12], their promising preclinical efficacy as anti-cancer agents has not been consistently observed in the clinic [12]. A greater understanding of the cellular and molecular processes that mediate the beneficial and detrimental outcomes of TLR signaling is needed in order to optimize the translation of this approach. Spontaneous remissions of acute lymphoblastic leukemia (ALL) associated with se...

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“…They also act as an important bridge between the processes involved in innate and acquired immunity (Akira et al 2001;Bollmer et al 2011). TLRs are typically composed of a pathogenrecognition extracellular domain, a short transmembrane segment and an intracellular toll/interleukin-1 signalling domain (Gay and Gangloff 2007;Werling et al 2009;Alcaide and Edwards 2011). The extracellular signalling domain is composed of a leucine-rich repeat motif which plays a vital role in detecting the distinctive features of invading microbes, so called ''pathogen associated molecular patterns'' (Takeuchi et al 1999;Werling et al 2009;Alcaide and Edwards 2011;Tschirren et al 2013).…”

Section: Introductionmentioning

confidence: 99%

“…TLRs are typically composed of a pathogenrecognition extracellular domain, a short transmembrane segment and an intracellular toll/interleukin-1 signalling domain (Gay and Gangloff 2007;Werling et al 2009;Alcaide and Edwards 2011). The extracellular signalling domain is composed of a leucine-rich repeat motif which plays a vital role in detecting the distinctive features of invading microbes, so called ''pathogen associated molecular patterns'' (Takeuchi et al 1999;Werling et al 2009;Alcaide and Edwards 2011;Tschirren et al 2013). Once bound to an invading pathogen, TLRs orchestrate the first volley of immune defence by initiating a signalling cascade which is mediated by specific adaptor proteins (Akira et al 2001;Alcaide and Edwards 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Several of these TLR genes are thought to evolve under the effects of balancing selection (Ferrer-Admetlla et al 2008) and show high levels of allelic variation (Alcaide and Edwards 2011;Bergman et al 2012;Grueber et al 2012). One of the best characterised TLRs is toll-like receptor 4 (Tlr4), which recognises lipopolysaccharides in the outer membrane of gram negative bacteria (Akira et al 2001;Shi et al 2006;Werling et al 2009). As Tlr4 is known to play an important role in a host's defence against parasites, genetic polymorphism at this locus has been recognised as a potential candidate for investigating the signatures of selection acting upon innate immune defence genes in natural populations (Hughes and Friedman 2008;Tschirren et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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Gene dynamics of toll-like receptor 4 through a population bottleneck in an insular population of water voles (Arvicola amphibius)

et al. 2015

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Understanding the extent to which diversity at immunologically important genes is reduced by demographic perturbations such as population bottlenecks, and the resulting consequences this has on individual fitness, is of fundamental importance for the effective management of genetic resources in natural populations. Toll-like receptors are key immunological genes with well-established links to fitness. Here, levels of allelic diversity and heterozygosity at the toll-like receptor 4 locus (Tlr4) were characterised across 280 water voles (Arvicola amphibius) from an isolated, island population in north west Scotland that went through a severe population bottleneck between 2004 and 2006 that eroded neutral microsatellite variation. Two functional Tlr4 alleles were resolved prior to the population crash at frequencies close to parity and an excess of heterozygote genotypes relative to Hardy-Weinberg expectations. Through the population bottleneck both alleles were retained with genotype frequencies conforming to Hardy-Weinberg expectations. Tlr4 genotype was significantly associated with gamasid mite, flea (Megabothris walkeri) and sheep tick larva (Ixodes ricinus) burdens among individuals, suggesting a mechanism through which parasite mediated selection could affect Tlr4 diversity. The results are examined with recourse to the extent that they are consistent with the effects of genetic drift and balancing selection, and their significance is discussed in relation to identifying target genes that assay ecological and adaptively meaningful genetic variation in a conservation context.

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Variation matters: TLR structure and species-specific pathogen recognition

Cited by 233 publications

References 50 publications

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

Gene dynamics of toll-like receptor 4 through a population bottleneck in an insular population of water voles (Arvicola amphibius)

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