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

• Published in: International immunopharmacology Vol. 84; p. 106555
• Main Authors: Al-Harbi, Naif O., Nadeem, Ahmed, Ahmad, Sheikh F., AL-Ayadhi, Laila Y., Al-Harbi, Mohammad M., As Sobeai, Homood M., Ibrahim, Khalid E., Bakheet, Saleh A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2020; Elsevier BV
• Subjects: Agammaglobulinaemia Tyrosine Kinase - immunology; Autism; Autistic children; Autistic Disorder - immunology; B cells; B-Lymphocytes - immunology; Bruton's tyrosine kinase; Cell interactions; Child; Children; Communication skills; CYBB protein; Female; Humans; Immune system; Inflammation; Kinases; Lipopolysaccharides; Lymphocytes B; Male; NAD(P)H oxidase; NADPH oxidase; NADPH Oxidase 2 - immunology; Neurodevelopmental disorders; NF-kappa B - immunology; NF-κB protein; Nitrotyrosine; Nuclear factor kappa B; Oxidants; Oxidase; Oxidative stress; Oxidative Stress - immunology; Oxidizing agents; Protein-tyrosine kinase; Proteins; Receptors; Signaling; Social behavior; Spleen; Superoxide dismutase; Syk Kinase - immunology; Syk protein; TLR4 protein; Toll-like receptor 4; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Toll-like receptors; Tyrosine; Autism; B cells; Oxidants; NADPH oxidase; Toll-like receptor 4; Nuclear factor kappa B
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2020.106555

•B cells of children with autism spectrum disorder (ASD) had increased TLR4/NF-kB expression.•B cells of children with ASD had increased expression of NADPH oxidase.•B cells of children with ASD had deficiency of enzymatic antioxidants.•NF-kB inhibition reduced LPS-induced NOX2 upregulation in ASD B cells. 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.