Elevated expression of toll-like receptor 4 is associated with NADPH oxidase-induced oxidative stress in B cells of children with autism

Abstract

Autism spectrum disorder (ASD) is a childhood disorder with neurodevelopmental dysfunction which manifests as impairment in social behavior and communication skills. B cells play an important role in immune dysfunction where toll-like receptor 4 (TLR4) may contribute through oxidative inflammatory process. TLR4 related signaling and oxidative stress have been reported in the periphery of ASD subjects, however it has not been evaluated in peripheral B cells of ASD subjects and compared with typically developing control (TDC) children. This study evaluated TLR4 expression and related signaling [Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), NF-kB, NADPH oxidase (NOX2), nitrotyrosine, superoxide dismutase (SOD)] in ASD and TDC subjects. Current investigation in B cells shows that ASD subjects have increased TLR4 expression and oxidative stress as exhibited by upregulated NOX2 and nitrotyrosine expression as compared to TDC subjects. B cell relevant pathways, BTK/SYK/NF-kB were also upregulated in B cells of ASD group. Treatment with TLR4 agonist, LPS led to upregulation of NOX2 and nitrotyrosine in B cells of ASD whereas it had no significant effect on TDC subjects. Treatment with NF-kB inhibitor caused inhibition of LPS-induced upregulation of NOX2 and nitrotyrosine in B cells of ASD. Therefore, current investigation proposes the notion that TLR4 expression is elevated in B cells which is associated with increased NF-kB signaling and oxidant stress in ASD subjects. In short, peripheral B cells could contribute to systemic oxidative inflammation and contribute to the immune dysfunction in ASD.