Activation of IL-17 receptor leads to increased oxidative inflammation in peripheral monocytes of autistic children

• Published in: Brain, behavior, and immunity Vol. 67; pp. 335 - 344
• Main Authors: Nadeem, Ahmed, Ahmad, Sheikh F., Attia, Sabry M., Bakheet, Saleh A., Al-Harbi, Naif O., AL-Ayadhi, Laila Y.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.01.2018
• Subjects: Autism; Autism Spectrum Disorder - complications; Autism Spectrum Disorder - metabolism; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; IL-17 receptor; Inducible nitric oxide synthase; Inflammation - complications; Inflammation - metabolism; Interleukin-17 - administration & dosage; Interleukin-17 - metabolism; Leukocytes, Mononuclear - metabolism; Male; Monocytes; NF-kappa B - metabolism; Oxidative inflammation; Oxidative Stress; Receptors, Interleukin-17 - metabolism; Autism; ASD; TDC; Monocytes; NFκB; IL-17A; IL-17 receptor; Inducible nitric oxide synthase; Oxidative inflammation; IL-17R; iNOS
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2017.09.010

•Autistic children have increased IL-17 receptor expression in monocytes.•iNOS/nitrotyrosine expression is also higher in monocytes of autistic children.•Activation of IL-17 receptor enhances oxidative inflammation in autistic children.•Blockade of IL-17 receptor attenuates oxidative inflammation in autistic children. Millions of children are affected by different neurodevelopmental disorders, out of which autism spectrum disorder (ASD) poses a major hurdle to normal life style due to associated behavioral abnormalities. Several studies have shown an increased expression/release of Th17 related cytokine, IL-17A in ASD. IL-17A may enhance neuroinflammation via its IL-17A receptor, i.e. IL-17RA expressed in immune cells (such as monocytes) of autistic children. Increased oxidative stress has been implicated in a number of neuropsychiatric disorders including ASD. However, whether IL-17A/IL-17RA signaling contributes to oxidative inflammation in monocytes of autistic children has not been explored previously. With this background, we performed this study in peripheral monocytes of ASD patients and age-matched typically developing children. Our study shows that ASD individuals have increased IL-17RA expression in monocytes which is associated with increased nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway and inducible nitric oxide synthase (iNOS)/nitrotyrosine expression as compared to typically developing children. Moreover, in vitro activation of IL-17 receptor by IL-17A in monocytes isolated from ASD individuals leads to enhanced iNOS expression via NFκB pathway. IL-17RA antibody treatment in vitro reversed IL-17A-induced increase in NFκB and iNOS/nitrotyrosine expression in monocytes isolated from ASD subjects. These data connect increased IL-17A/IL-17RA signaling in ASD patients with enhanced oxidative inflammation in monocytes. Therefore, IL-17 receptor signaling in monocytes may potentiate the effects of IL-17A released by other immune cells and may aggravate neuroinflammation in ASD. Our study further suggests that blockade of IL-17A/IL-17 receptor signaling may be beneficial in the children with ASD.