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...

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Main Authors: Dean Huggard, W. J. Koay, Lynne Kelly, Fiona McGrane, Emer Ryan, Niamh Lagan, Edna Roche, Joanne Balfe, T. Ronan Leahy, Orla Franklin, Ana Moreno-Oliveira, Ashanty M. Melo, Derek G. Doherty, Eleanor J. Molloy
Format: Article
Language:English
Published: Hindawi Limited 2019-01-01
Series:Mediators of Inflammation
Online Access:http://dx.doi.org/10.1155/2019/4068734
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spelling doaj-cd7766bc5e2d439aac2a2e1030b657d02020-11-24T21:49:13ZengHindawi LimitedMediators of Inflammation0962-93511466-18612019-01-01201910.1155/2019/40687344068734Altered Toll-Like Receptor Signalling in Children with Down SyndromeDean Huggard0W. J. Koay1Lynne Kelly2Fiona McGrane3Emer Ryan4Niamh Lagan5Edna Roche6Joanne Balfe7T. Ronan Leahy8Orla Franklin9Ana Moreno-Oliveira10Ashanty M. Melo11Derek G. Doherty12Eleanor J. Molloy13Paediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandPaediatrics, Trinity College, The University of Dublin, Dublin, IrelandToll-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.http://dx.doi.org/10.1155/2019/4068734
collection DOAJ
language English
format Article
sources DOAJ
author Dean Huggard
W. J. Koay
Lynne Kelly
Fiona McGrane
Emer Ryan
Niamh Lagan
Edna Roche
Joanne Balfe
T. Ronan Leahy
Orla Franklin
Ana Moreno-Oliveira
Ashanty M. Melo
Derek G. Doherty
Eleanor J. Molloy
spellingShingle Dean Huggard
W. J. Koay
Lynne Kelly
Fiona McGrane
Emer Ryan
Niamh Lagan
Edna Roche
Joanne Balfe
T. Ronan Leahy
Orla Franklin
Ana Moreno-Oliveira
Ashanty M. Melo
Derek G. Doherty
Eleanor J. Molloy
Altered Toll-Like Receptor Signalling in Children with Down Syndrome
Mediators of Inflammation
author_facet Dean Huggard
W. J. Koay
Lynne Kelly
Fiona McGrane
Emer Ryan
Niamh Lagan
Edna Roche
Joanne Balfe
T. Ronan Leahy
Orla Franklin
Ana Moreno-Oliveira
Ashanty M. Melo
Derek G. Doherty
Eleanor J. Molloy
author_sort Dean Huggard
title Altered Toll-Like Receptor Signalling in Children with Down Syndrome
title_short 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_sort altered toll-like receptor signalling in children with down syndrome
publisher Hindawi Limited
series Mediators of Inflammation
issn 0962-9351
1466-1861
publishDate 2019-01-01
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.
url http://dx.doi.org/10.1155/2019/4068734
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