Plasma Extracellular Vesicles (EVs)-Mediated Immune Dysregulation and Chronic Inflammation in Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by repetitive behaviors, communication deficits, and frequent comorbidities. While both genetic and environmental factors contribute to ASD etiology, immune dysregulation has emerged as a potential environmental driver, suggesting a critical role of chronic inflammation in ASD pathophysiology. We previously demonstrated that ASD individuals display specific changes in plasma EV cargo which is associated with immune dysregulation. Here, we show that ASD EVs contain dysregulated cytokine profiles, including Gro-alpha/CXCL1, RANTES/CCL5, IFN-gamma, stem cell growth factor beta (SCGF-beta), and IL-15. Notably, ASD EVs enhance IFN-gamma secretion from peripheral blood lymphocytes (PBLs) in direct co-cultures, which can be reversed by treatment with the anti-inflammatory agent dexamethasone (Dex). Our findings suggest that ASD EVs contribute to chronic inflammation and highlight a potential therapeutic target for ASD intervention by mitigating ASD EV-induced chronic inflammation.