Altered Toll-Like Receptor Signalling in Children with Down Syndrome.

Abstract

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.

• 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
• Journal: Mediators of inflammation (Mediators Inflamm) Vol. 2019 Pg. 4068734 ( 2019) ISSN: 1466-1861 [Electronic] United States
• PMID: 31611734 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Dean Huggard et al.

Chemical References

• CD11b Antigen
• Heterocyclic Compounds, 4 or More Rings
• Lipopolysaccharides
• Toll-Like Receptor 2
• Toll-Like Receptors
• sparstolonin B
• IRAK4 protein, human
• Interleukin-1 Receptor-Associated Kinases

Topics

• Adolescent
• Autoimmunity
• CD11b Antigen (metabolism)
• Child
• Child, Preschool
• Down Syndrome (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Immunity, Innate (drug effects)
• Interleukin-1 Receptor-Associated Kinases (metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Monocytes (drug effects, metabolism)
• Neutrophils (drug effects, metabolism)
• Signal Transduction (drug effects)
• Toll-Like Receptor 2 (metabolism)
• Toll-Like Receptors (antagonists & inhibitors)