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Human TLR10 is an anti-inflammatory pattern-recognition receptor.

ABSTRACT: Toll-like receptor (TLR)10 is the only pattern-recognition receptor without known ligand specificity and biological function. We demonstrate that TLR10 is a modulatory receptor with mainly inhibitory effects. Blocking TLR10 by antagonistic antibodies enhanced proinflammatory cytokine production, including IL-1?, specifically after exposure to TLR2 ligands. Blocking TLR10 after stimulation of peripheral blood mononuclear cells with pam3CSK4 (Pam3Cys) led to production of 2,065 ± 106 pg/mL IL-1? (mean ± SEM) in comparison with 1,043 ± 51 pg/mL IL-1? after addition of nonspecific IgG antibodies. Several mechanisms mediate the modulatory effects of TLR10: on the one hand, cotransfection in human cell lines showed that TLR10 acts as an inhibitory receptor when forming heterodimers with TLR2; on the other hand, cross-linking experiments showed specific induction of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra, 16 ± 1.7 ng/mL, mean ± SEM). After cross-linking anti-TLR10 antibody, no production of IL-1? and other proinflammatory cytokines could be found. Furthermore, individuals bearing TLR10 polymorphisms displayed an increased capacity to produce IL-1?, TNF-?, and IL-6 upon ligation of TLR2, in a gene-dose-dependent manner. The modulatory effects of TLR10 are complex, involving at least several mechanisms: there is competition for ligands or for the formation of heterodimer receptors with TLR2, as well as PI3K/Akt-mediated induction of the anti-inflammatory cytokine IL-1Ra. Finally, transgenic mice expressing human TLR10 produced fewer cytokines when challenged with a TLR2 agonist. In conclusion, to our knowledge we demonstrate for the first time that TLR10 is a modulatory pattern-recognition receptor with mainly inhibitory properties.

SUBMITTER: Oosting M

PROVIDER: S-EPMC4210319 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Human TLR10 is an anti-inflammatory pattern-recognition receptor.

Oosting Marije M Cheng Shih-Chin SC Bolscher Judith M JM Vestering-Stenger Rachel R Plantinga Theo S TS Verschueren Ineke C IC Arts Peer P Garritsen Anja A van Eenennaam Hans H Sturm Patrick P Kullberg Bart-Jan BJ Hoischen Alexander A Adema Gosse J GJ van der Meer Jos W M JW Netea Mihai G MG Joosten Leo A B LA

Proceedings of the National Academy of Sciences of the United States of America 20141006 42

Toll-like receptor (TLR)10 is the only pattern-recognition receptor without known ligand specificity and biological function. We demonstrate that TLR10 is a modulatory receptor with mainly inhibitory effects. Blocking TLR10 by antagonistic antibodies enhanced proinflammatory cytokine production, including IL-1β, specifically after exposure to TLR2 ligands. Blocking TLR10 after stimulation of peripheral blood mononuclear cells with pam3CSK4 (Pam3Cys) led to production of 2,065 ± 106 pg/mL IL-1β ( ...[more]

PMID: 25288745

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Project description:Background and aimsA number of antibodies against microbial epitopes or self-antigens have been associated with Crohn's disease. The development of antibodies reflects a loss of tolerance to intestinal bacteria that underlies Crohn's disease, resulting in an exaggerated adaptive immune response to these bacteria. It was hypothesised that the development of antimicrobial antibodies is influenced by the presence of genetic variants in pattern recognition receptor genes. The aim of this study was therefore to investigate the influence of mutations in these innate immune receptor genes (nucleotide oligomerisation domain (NOD) 2/caspase recruitment domain (CARD) 15, NOD1/CARD4, TUCAN/CARDINAL/CARD8, Toll-like receptor (TLR) 4, TLR2, TLR1 and TLR6) on the development of antimicrobial and antiglycan antibodies in inflammatory bowel disease (IBD).Materials and methodsA cohort of 1163 unrelated patients with IBD (874 Crohn's disease, 259 ulcerative colitis, 30 indeterminate colitis) and 312 controls were analysed for anti-Saccharomyces cerevisiae antibodies (gASCA) IgG, anti-laminaribioside antibodies (ALCA) IgG, anti-chitobioside antibodies (ACCA) IgA, anti-mannobioside antibodies (AMCA) IgG and outer membrane porin (Omp) IgA and were genotyped for variants in NOD2/CARD15, TUCAN/CARDINAL/CARD8, NOD1/CARD4, TLR4, TLR1, TLR2 and TLR6.ResultsWhen compared with Crohn's disease patients without CARD15 mutations, the presence of at least one CARD15 variant in Crohn's disease patients more frequently led to gASCA positivity (66.1% versus 51.5%, p < 0.0001) and ALCA positivity (43.3% versus 34.9%, p = 0.018) and higher gASCA titers (85.7 versus 51.8 ELISA units, p < 0.0001), independent of ileal involvement. A gene dosage effect, with increasing gASCA and ALCA positivity for patients carrying none, one and two CARD15 variants, respectively, was seen for both markers. Similarly, Crohn's disease patients carrying NOD1/CARD4 indel had a higher prevalence of gASCA antibodies than wild-type patients (63.8% versus 55.2%, p = 0.014), also with a gene dosage effect. An opposite effect was observed for the TLR4 D299G and TLR2 P631H variants, with a lower prevalence of ACCA antibodies (23.4% versus 35%, p = 0.013) and Omp antibodies (20.5% versus 34.6%, p = 0.009), respectively.ConclusionVariants in innate immune receptor genes were found to influence antibody formation against microbial epitopes. In this respect, it is intriguing that an opposite effect of CARD15 and TLR4 variants was observed. These findings may contribute to an understanding of the aetiology of the seroreactivity observed in IBD.

Dataset Information

Human TLR10 is an anti-inflammatory pattern-recognition receptor.

Publications

Human TLR10 is an anti-inflammatory pattern-recognition receptor.

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