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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.
Highlights
Down syndrome (DS) is caused by extra genetic material from chromosome 21 and is the most common of the chromosomal abnormalities affecting 1 in 700 births in the USA [1]
Activation of these Toll-like receptors (TLRs) initiates downstream signalling pathways and recruitment of a constellation of adaptor proteins: myeloid differentiation primary response gene 88 (MyD88), MyD88 adaptor-like protein (MAL), IL-1R-associated kinase (IRAK) family, and TIR-domain-containing adaptor protein-inducing interferon-β (TRIF), which in turn stimulate downstream kinases (JNK, ERK, and MAPKs), leading to nuclear translocation of an increase in the transcription factors, including nuclear factor kappa B (NF-κB) and interferon regulatory factor-3 (IRF-3), leading to the production of proinflammatory cytokines [11]. Strict regulation of these TLR pathways is crucial in achieving protection from infection and avoiding damage from excess cytokine production which can lead to worse outcomes, acutely in sepsis or in chronic inflammation resulting in autoimmunity, both of these sequelae occurring more frequently in DS [12, 13]
We aimed to evaluate TLR pathways in 3 ways: by determining the expression of TLR2 on the surface of neutrophils, monocytes, and their subsets, by examining the gene expression of key regulatory proteins involved in TLR signal propagation, MyD88, IRAK4, and TRIF, and lastly by determining the cytokine production at baseline and following immunomodulation with proinflammatory stimuli (LPS, Pam3Csk4) and the anti-inflammatory agent Sparstolonin B (SsnB)
Summary
Down syndrome (DS) is caused by extra genetic material from chromosome 21 and is the most common of the chromosomal abnormalities affecting 1 in 700 births in the USA [1]. Toll-like receptors (TLRs) and their activation are crucial in initiating the innate immune response, while linking the adaptive response to infection [10] Activation of these TLRs initiates downstream signalling pathways and recruitment of a constellation of adaptor proteins: myeloid differentiation primary response gene 88 (MyD88), MyD88 adaptor-like protein (MAL), IL-1R-associated kinase (IRAK) family, and TIR-domain-containing adaptor protein-inducing interferon-β (TRIF), which in turn stimulate downstream kinases (JNK, ERK, and MAPKs), leading to nuclear translocation of an increase in the transcription factors, including nuclear factor kappa B (NF-κB) and interferon regulatory factor-3 (IRF-3), leading to the production of proinflammatory cytokines [11]. Strict regulation of these TLR pathways is crucial in achieving protection from infection and avoiding damage from excess cytokine production which can lead to worse outcomes, acutely in sepsis or in chronic inflammation resulting in autoimmunity, both of these sequelae occurring more frequently in DS [12, 13]
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