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Altered Toll-Like Receptor Signalling in Children with Down Syndrome
Toll-like receptors (TLRs) are the key in initiating innate immune responses. TLR2 is crucial in recognising lipopeptides from gram-positive bacteria and is implicated in chronic inflammation. Children with Down syndrome (DS) are prone to infections from these pathogens and have an increased risk of...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757445/ https://www.ncbi.nlm.nih.gov/pubmed/31611734 http://dx.doi.org/10.1155/2019/4068734 |
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author | Huggard, Dean Koay, W. J. Kelly, Lynne McGrane, Fiona Ryan, Emer Lagan, Niamh Roche, Edna Balfe, Joanne Leahy, T. Ronan Franklin, Orla Moreno-Oliveira, Ana Melo, Ashanty M. Doherty, Derek G. Molloy, Eleanor J. |
author_facet | Huggard, Dean Koay, W. J. Kelly, Lynne McGrane, Fiona Ryan, Emer Lagan, Niamh Roche, Edna Balfe, Joanne Leahy, T. Ronan Franklin, Orla Moreno-Oliveira, Ana Melo, Ashanty M. Doherty, Derek G. Molloy, Eleanor J. |
author_sort | Huggard, Dean |
collection | PubMed |
description | Toll-like receptors (TLRs) are the key in initiating innate immune responses. TLR2 is crucial in recognising lipopeptides from gram-positive bacteria and is implicated in chronic inflammation. Children with Down syndrome (DS) are prone to infections from these pathogens and have an increased risk of autoimmunity. Sparstolonin B (SsnB) is a TLR antagonist which attenuates cytokine production and improves outcomes in sepsis. We hypothesised that TLR signalling may be abnormal in children with DS and contribute to their clinical phenotype. We evaluated TLR pathways in 3 ways: determining the expression of TLR2 on the surface of neutrophils and monocytes by flow cytometry, examining the gene expression of key regulatory proteins involved in TLR signal propagation, MyD88, IRAK4, and TRIF, by quantitative PCR, and lastly determining the cytokine production by ELISA following immunomodulation with proinflammatory stimuli (lipopolysaccharide (LPS), Pam3Csk4) and the anti-inflammatory agent SsnB. We report TLR2 expression being significantly increased on neutrophils, total monocytes, and intermediate and nonclassical monocytes in children with DS (n = 20, mean age 8.8 ± SD 5.3 years, female n = 11) compared to controls (n = 15, mean age 6.2 ± 4.2 years, female n = 5). At baseline, the expression of MyD88 was significantly lower, and TRIF significantly raised in children with DS. The TLR antagonist SsnB was effective in reducing TLR2 and CD11b expression and abrogating cytokine production in both cohorts. We conclude that TLR signalling and the TLR2 pathway are dysregulated in DS, and this disparate innate immunity may contribute to chronic inflammation in DS. SsnB attenuates proinflammatory mediators and may be of therapeutic benefit. |
format | Online Article Text |
id | pubmed-6757445 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-67574452019-10-14 Altered Toll-Like Receptor Signalling in Children with Down Syndrome Huggard, Dean Koay, W. J. Kelly, Lynne McGrane, Fiona Ryan, Emer Lagan, Niamh Roche, Edna Balfe, Joanne Leahy, T. Ronan Franklin, Orla Moreno-Oliveira, Ana Melo, Ashanty M. Doherty, Derek G. Molloy, Eleanor J. Mediators Inflamm Research Article Toll-like receptors (TLRs) are the key in initiating innate immune responses. TLR2 is crucial in recognising lipopeptides from gram-positive bacteria and is implicated in chronic inflammation. Children with Down syndrome (DS) are prone to infections from these pathogens and have an increased risk of autoimmunity. Sparstolonin B (SsnB) is a TLR antagonist which attenuates cytokine production and improves outcomes in sepsis. We hypothesised that TLR signalling may be abnormal in children with DS and contribute to their clinical phenotype. We evaluated TLR pathways in 3 ways: determining the expression of TLR2 on the surface of neutrophils and monocytes by flow cytometry, examining the gene expression of key regulatory proteins involved in TLR signal propagation, MyD88, IRAK4, and TRIF, by quantitative PCR, and lastly determining the cytokine production by ELISA following immunomodulation with proinflammatory stimuli (lipopolysaccharide (LPS), Pam3Csk4) and the anti-inflammatory agent SsnB. We report TLR2 expression being significantly increased on neutrophils, total monocytes, and intermediate and nonclassical monocytes in children with DS (n = 20, mean age 8.8 ± SD 5.3 years, female n = 11) compared to controls (n = 15, mean age 6.2 ± 4.2 years, female n = 5). At baseline, the expression of MyD88 was significantly lower, and TRIF significantly raised in children with DS. The TLR antagonist SsnB was effective in reducing TLR2 and CD11b expression and abrogating cytokine production in both cohorts. We conclude that TLR signalling and the TLR2 pathway are dysregulated in DS, and this disparate innate immunity may contribute to chronic inflammation in DS. SsnB attenuates proinflammatory mediators and may be of therapeutic benefit. Hindawi 2019-09-12 /pmc/articles/PMC6757445/ /pubmed/31611734 http://dx.doi.org/10.1155/2019/4068734 Text en Copyright © 2019 Dean Huggard et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Huggard, Dean Koay, W. J. Kelly, Lynne McGrane, Fiona Ryan, Emer Lagan, Niamh Roche, Edna Balfe, Joanne Leahy, T. Ronan Franklin, Orla Moreno-Oliveira, Ana Melo, Ashanty M. Doherty, Derek G. Molloy, Eleanor J. Altered Toll-Like Receptor Signalling in Children with Down Syndrome |
title | Altered Toll-Like Receptor Signalling in Children with Down Syndrome |
title_full | Altered Toll-Like Receptor Signalling in Children with Down Syndrome |
title_fullStr | Altered Toll-Like Receptor Signalling in Children with Down Syndrome |
title_full_unstemmed | Altered Toll-Like Receptor Signalling in Children with Down Syndrome |
title_short | Altered Toll-Like Receptor Signalling in Children with Down Syndrome |
title_sort | altered toll-like receptor signalling in children with down syndrome |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757445/ https://www.ncbi.nlm.nih.gov/pubmed/31611734 http://dx.doi.org/10.1155/2019/4068734 |
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