sparstolonin-b and 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 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 (

Topics: Adolescent; Autoimmunity; CD11b Antigen; Child; Child, Preschool; Down Syndrome; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Heterocyclic Compounds, 4 or More Rings; Humans; Immunity, Innate; Interleukin-1 Receptor-Associated Kinases; Lipopolysaccharides; Male; Monocytes; Neutrophils; Signal Transduction; Toll-Like Receptor 2; Toll-Like Receptors