Altered toll-like receptor expression in autism spectrum disorder: Evidence from mRNA and serum protein analyses

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition in which immune dysregulation and neuroinflammatory processes are increasingly implicated. Toll-like receptors (TLRs), as key components of innate immunity, may represent a biological interface between peripheral immune activity and neurobehavioral manifestations; however, comprehensive investigations of the full TLR family in ASD remain scarce. This study aimed to evaluate peripheral blood mRNA expression of all human TLRs (TLR1-TLR10) and corresponding serum protein levels in children and adolescents with ASD. Thirty-one drug-naive participants with ASD and 31 age- and sex-matched healthy controls aged 4-18 years were enrolled. Clinical assessments included the Childhood Autism Rating Scale (CARS) and the Aberrant Behavior Checklist (ABC). TLR mRNA expression was quantified using RT-qPCR, and serum protein levels were measured by ELISA. The ASD group exhibited significantly higher mRNA expression of TLR1, TLR4, TLR5, and TLR8 and lower expression of TLR6 (all p < .01). Concordantly, serum protein levels of TLR1, TLR4, TLR5, and TLR8 were increased, whereas TLR6 levels were decreased (all p < .001). No differences were observed for TLR2, TLR3, TLR7, TLR9, or TLR10. Circulating levels of TLR1, TLR4, TLR5, TLR6, and TLR8 were significantly associated with ASD severity and behavioral symptoms (p < .05). These findings provide novel evidence of coordinated alterations in multiple TLR subtypes in ASD beyond previously reported TLR4 dysregulation. The results suggest that TLR-mediated innate immune signaling may be linked to clinical symptomatology and highlight specific TLRs as potential targets for future biomarker-oriented research.