Identification of TLR10 as a Key Mediator of the Inflammatory Response to <i>Listeria monocytogenes</i> in Intestinal Epithelial Cells and Macrophages

Regan, Tim; Nally, Ken; Carmody, Ruaidhrı́ J.; Houston, Aileen; Shanahan, Fergus; MacSharry, John; Brint, Elizabeth

doi:10.4049/jimmunol.1203245

Cited by 96 publications

(87 citation statements)

References 35 publications

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“…Mulla et al also found the trigger for this response to be a TLR2 ligand (i.e., peptidoglycan); no effect on IL-6 production was found in these studies (7). Very recently, a study described that TLR10 acts as a proinflammatory TLR, which is the opposite of the suppressive function of TLR10 we report here (19 PBMCs from individuals without polymorphisms (wt; wild-type; white bars), individuals with the I369L SNP (D) or I775V SNP (E) in one of both alleles (he; heterozygous; gray bars), and individuals with the SNP in both alleles (ho; homozygous; black bars), were stimulated for 24 h at 37°C with RPMI, or B. burgdorferi. IL-1Ra was measured in the supernatant using ELISA.…”

Section: Discussionmentioning

confidence: 43%

Human TLR10 is an anti-inflammatory pattern-recognition receptor

Oosting¹,

Cheng²,

Bolscher

et al. 2014

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

208

210

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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 (mean ± SEM) in comparison with 1,043 ± 51 pg/mL IL-1β 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-1β and other proinflammatory cytokines could be found. Furthermore, individuals bearing TLR10 polymorphisms displayed an increased capacity to produce IL-1β, TNF-α, 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/Aktmediated 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.ighly conserved molecular structures of invading microorganisms are recognized by immune cells through patternrecognition receptors, of which Toll-like receptors (TLRs) are the most documented family. In humans, 10 members of the TLR family have been described (1). In general, specific ligation of TLRs leads to induction of proinflammatory mediators, such as cytokines and chemokines. One member of the TLR family however, TLR10, is considered an orphan receptor because of its still-unknown ligands and function.Human TLR10 is encoded on chromosome 4 within the TLR2 gene cluster, together with TLR1, TLR2, and TLR6, and shares all structural characteristics of the TLR family (2, 3). However, TLR10 differs from other TLRs by its lack of a classic downstream signaling pathway (4), despite its interaction with the myeloid differentiation primary response gene 88 adaptor protein (3). TLR10 is predominantly expressed in tissues rich in immune cells, such as spleen, lymph node, thymus, tonsil, and lung (2). Expression of TLR10 can be induced in B cells, dendritic cells, eosinophils, and neutrophils (3, 5, 6), as well as on nonimmune cells, such as trophoblasts (7). TLR1 and TLR6 are known to form heterodimers with TLR2, and this was shown for TLR10 as well (3,8). It is therefore ...

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Section: Discussionmentioning

confidence: 43%

Human TLR10 is an anti-inflammatory pattern-recognition receptor

Oosting¹,

Cheng²,

Bolscher

et al. 2014

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

208

210

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“…TLR5 primarily senses flagelin, a structural component of flagellated bacteria . Human TLR10 recognizes ligands from listeria in collaboration with TLR2 (Regan et al, 2013), whereas mouse TLR10 contains a stop codon and, thus, it is a pseudogene (Kawasaki and Kawai, 2014). TLR10 also responds to influenza A virus infection (Lee et al, 2014).…”

Section: A Structure and Functionmentioning

confidence: 99%

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

2015

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“…TLR4 recognizes lipopolysaccharide (LPS) from Gram-negative bacteria such as E. coli, while TLR5 binds to flagellin. The ligand for TLR10 is still not known (Hirata et al, 2007;Regan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Characterization and Transcriptional Profile of Toll-Like Receptors of Bubalus bubalis with Endometritis

Osman¹

2015

J. Inf. Mol. Biol.

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| Toll-like receptors (TLRs) are a vital component of innate immune system and perform an important role in disease resistance through recognition of pathogen associated molecular patterns (PAMPs) and initiation of a convenient immune response. Endometritis is the most important disease causing infertility in cattle and buffalo and TLRs play a critical role in elimination of that disease. The present study aims to characterize the transcripts of TLRs: TLR1, TLR2, TLR4, TLR6 and TLR10 in Bubalus bubalis with endometritis. Quantitative real-time (q-PCR) assays were performed to detect transcript expression profiles of these TLRs in liver, mammary gland, ovary and uterus of Bubalus bubalis with and without endometritis. The result showed that the transcript profiles of TLRs especially TLR2 and TLR4 were significantly differences in mammary glands, ovary and uterus but on the othe hands, there is no significant difference in the transcript profile of TLRs in liver with or without endometritis. TLRs nucleotide sequences have more than 97% nucleotide homology between Bubalus bubalis with and without endometritis. Simple modular architecture tool (SMART) analysis revealed the presence of TIR domains and different numbers of leucine rich repeat motifs in tested TLRs. In conclusion, for animals infected with endometritis, there was a significant difference of TLR2 and TLR4 in uterine tissue compared to uninfected animals. Therefore, it is suggested to consider the TLRs results as detection markers for endometritis.

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Identification of TLR10 as a Key Mediator of the Inflammatory Response to Listeria monocytogenes in Intestinal Epithelial Cells and Macrophages

Cited by 96 publications

References 35 publications

Human TLR10 is an anti-inflammatory pattern-recognition receptor

Human TLR10 is an anti-inflammatory pattern-recognition receptor

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

Characterization and Transcriptional Profile of Toll-Like Receptors of Bubalus bubalis with Endometritis

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