title: Toll-like receptor 4 signaling is associated with upregulated NADPH oxidase expression in peripheral T cells of children with autism.
abstract: Autism spectrum disorders (ASD) affect millions of children worldwide, and are characterized by impairment in social interaction and communication, and specific repetitive behavioral patterns. Growing evidence highlights a role of toll-like receptors (TLRs) in the pathogenesis of ASD. Specifically, TLR-4 activation has been shown to be associated with increased pro-inflammatory cytokines as well as autistic symptoms in offspring. NADPH oxidase (NOX-2) derived reactive oxygen species (ROS) have also been shown to play pathogenic role under inflammatory conditions. However, the role of TLR-4 in the regulation of NOX-2 derived ROS has not been explored in ASD, particularly in T cells. Therefore, this study explored TLR-4 and NOX-2 related signaling in peripheral T cells of ASD patients (n=35) and age-matched typically developing children (n=30). In this study, we find that ASD individuals have increased TLR-4 expression on T cells which is associated with increased NOX-2 expression and ROS generation as compared to typically developing children. Moreover, activation of TLR-4 on T cells by lipopolysaccharide (LPS) in vitro leads to enhanced generation of NOX-2 derived ROS via nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway. These data support a link between T cell TLR-4 activation and NOX-2/ROS upregulation in ASD patients. Our study has implications in the context of neuroinflammation observed in ASD patients as ROS may lead to amplification and perpetuation of inflammation both in the periphery and central nervous system. Our data also suggest that therapeutic targeting of TLR-4 signaling may lead to reduction in inflammation of ASD patients.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Electronic address: anadeem@ksu.edu.sa.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Nadeem
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Sheikh F
authors.initials: SF
authors.lastname: Ahmad
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Saleh A
authors.initials: SA
authors.lastname: Bakheet
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Naif O
authors.initials: NO
authors.lastname: Al-Harbi
authors.affiliation: Autism Research and Treatment Center, AL-Amodi Autism Research Chair, Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Laila Y
authors.initials: LY
authors.lastname: Al-Ayadhi
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Sabry M
authors.initials: SM
authors.lastname: Attia
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Cell Biology, National Research Centre, Cairo, Egypt.
authors.forename: Khairy M A
authors.initials: KMA
authors.lastname: Zoheir
mesh_terms: D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051197:Toll-Like Receptor 4; D019255:NADPH Oxidases
keywords: Autism; NADPH oxidase; Reactive oxygen species; T cell; Toll-like receptor 4