Human TLRs 10 and 1 Share Common Mechanisms of Innate Immune Sensing but Not Signaling

Guan, Yue; Rañoa, Diana Rose E.; Jiang, Siwei; Mutha, Sarita K.; Li, Xinyan; Baudry, Jérôme; Tapping, Richard I.

doi:10.4049/jimmunol.0901888

Cited by 213 publications

(262 citation statements)

References 76 publications

(106 reference statements)

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“…It remains the only member of the human TLR family without a defined agonist, signaling pathway, or function. Recent studies have suggested that TLR10 may be responsible for sensing of bacterial lipopeptides (12,25). Here we report that TLR10 acts as an innate immune sensing receptor for influenza virus infection.…”

Section: Discussionmentioning

confidence: 80%

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Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection

Lee

Kok

Jaume

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

153

126

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Toll-like receptors (TLRs) play key roles in innate immune recognition of pathogen-associated molecular patterns of invading microbes. Among the 10 TLR family members identified in humans, TLR10 remains an orphan receptor without known agonist or function. TLR10 is a pseudogene in mice and mouse models are noninformative in this regard. Using influenza virus infection in primary human peripheral blood monocyte-derived macrophages and a human monocytic cell line, we now provide previously unidentified evidence that TLR10 plays a role in innate immune responses following viral infection. Influenza virus infection increased TLR10 expression and TLR10 contributed to innate immune sensing of viral infection leading to cytokine induction, including proinflammatory cytokines and interferons. TLR10 induction is more pronounced following infection with highly pathogenic avian influenza H5N1 virus compared with a low pathogenic H1N1 virus. Induction of TLR10 by virus infection requires active virus replication and de novo protein synthesis. Culture supernatants of virus-infected cells modestly up-regulate TLR10 expression in nonvirus-infected cells. Signaling via TLR10 was activated by the functional RNA–protein complex of influenza virus leading to robust induction of cytokine expression. Taken together, our findings identify TLR10 as an important innate immune sensor of viral infection and its role in innate immune defense and immunopathology following viral and bacterial pathogens deserves attention.

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Section: Discussionmentioning

confidence: 80%

“…One study has suggested that TLR10 cooperates with TLR2 in sensing triacylated lipopeptides and recruits myeloid differentiation factor 88 (MyD88) to the activated receptor complex (12). However, they showed that native TLR10 coexpressed with TLR2 as a heterodimer in a human colonic epithelial cell line did not respond to lipopeptide stimulation.…”

mentioning

confidence: 99%

Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection

Lee

Kok

Jaume

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

153

126

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“…29) inducing both genes the nuclear factor-kb signaling pathways. Nevertheless, with respect to TLR10, Guan et al 30 recently demonstrated that, although TLR10 is a partner for TLR2 on the cell surface and it shares a variety of agonist with TLR1, however, it fails to activate the typical TLR-induced signaling including nuclear factor-kb and interferon-b. These data suggest that NOD2 and TLR10 have different signaling pathways, which would explain the independent effects of both loci in the susceptibility to CD.…”

Section: Discussionmentioning

confidence: 99%

Association of Toll-like receptor 10 and susceptibility to Crohn's disease independent of NOD2

et al. 2011

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Impaired innate inflammatory response has a key role in the Crohn's disease (CD) pathogenesis. The aim of this study was to investigate the possible role of the TLR10-TLR1-TLR6 gene cluster in CD susceptibility. A total of 508 CD patients (284, cohort 1 and 224, cohort 2) and 576 controls were included. TLR10-TLR1-TLR6 cluster single-nucleotide polymorphisms genotyping, NOD2 mutations and TLR10 mRNA quantification were performed using TaqMan assays. Nucleotide-binding oligomerization domain containing 2 (NOD2) and Toll-like receptor (TLR) loci interaction was analyzed by logistic regression and multifactor-dimensionality reduction (MDR). Entropy-based analysis was used to interpret combination effects. One TLR10 haplotype (TLR10 GGGG ) was found associated with CD susceptibility in both cohorts, individuals with two copies had approximately twofold more risk of CD susceptibility than individuals having no copies (odds ratio ¼ 1.89, P-value ¼ 0.0002). No differences in the mRNA levels were observed among the genotypes. The strongest model for predicting CD risk according to the MDR analysis was a two-locus model including NOD2 mutations and TLR10 GGGG haplotype (P c o0.0001). The interaction gain attributed to the combination of both genes was negative (IG ¼ À2.36%), indicating redundancy or independent effects. Our results support association of the TLR10 gene with CD susceptibility. The effect of TLR10 would be independent of NOD2, suggesting different signaling pathways for both genes.

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“…TLR10 is believed to form heterodimers with TLR2 in a similar mode to TLR1, as TLR10 exhibits conservation of key residues at the dimerization interface and a lipopeptide binding channel, though lipopeptide binding has not yet been shown to induce signaling [40]. No data is so far available to confirm a precise agonist for TLR10, and no crystal structure is available for the ectodomain, though it has been shown to be involved in the response to viral infections, particularly influenza A [41].…”

Section: Tlr10 Heterodimermentioning

confidence: 97%

“…No data is so far available to confirm a precise agonist for TLR10, and no crystal structure is available for the ectodomain, though it has been shown to be involved in the response to viral infections, particularly influenza A [41]. Homology modeling studies indicated that like TLR1-TLR2, the TLR10-TLR2 complex is likely to have a large hydrophobic core surrounded by hydrophilic residues stabilizing the dimer interface [40]. The residues predicted to be in the hydrophobic core are L342', Y320', Y313', V311', P339' and I359' on TLR10, and Y323, L324, F322, P352, Y376, L350, F349, L371 and V373 on TLR2.…”

Section: Tlr10 Heterodimermentioning

confidence: 99%

The role of protein–protein interactions in Toll-like receptor function

Berglund

Kargas

Ortiz-Suarez

et al. 2015

Progress in Biophysics and Molecular Biology

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As part of the innate immune system, the Toll-like receptors (TLRs) represent key players in the first line of defense against invading foreign pathogens, and are also major targets for therapeutic immunomodulation. TLRs are type I transmembrane proteins composed of an ectodomain responsible for ligand binding, a single-pass transmembrane domain, and a cytoplasmic Toll/Interleukin-1 receptor (TIR) signaling domain. The ectodomains of TLRs are specialized for recognizing a wide variety of pathogen-associated molecular patterns, ranging from lipids and lipopeptides to proteins and nucleic acid fragments. The members of the TLR family are highly conserved and their ectodomains are composed of characteristic, solenoidal leucine-rich repeats (LRRs). Upon ligand binding, these rigid LRR scaffolds dimerize (or re-organize in the case of pre-formed dimers) to bring together their carboxy-terminal transmembrane and TIR domains. The latter are proposed to act as a platform for recruitment of adaptor proteins and formation of higher-order complexes, resulting in propagation of downstream signaling cascades. In this review, we discuss the protein-protein interactions critical for formation and stability of productive, ligand-bound TLR complexes. In particular, we focus on the large body of high-resolution crystallographic data now available for the ectodomains of homo-and heterodimeric TLR complexes, as well as inhibitory TLR-like receptors, and also consider computational approaches that can facilitate our understanding of the ligand-induced conformational changes associated with TLR function. We also briefly consider what is known about the protein-protein interactions involved in both TLR transmembrane domain assembly and TIRmediated signaling complex formation in light of recent structural and biochemical data.

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Human TLRs 10 and 1 Share Common Mechanisms of Innate Immune Sensing but Not Signaling

Abstract: Material

Cited by 213 publications

References 76 publications

Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection

Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection

Association of Toll-like receptor 10 and susceptibility to Crohn's disease independent of NOD2

The role of protein–protein interactions in Toll-like receptor function

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