NLRP3 and RANK-RANKL-OPG Pathway-related Gene Expression Levels in Children With Autism Spectrum Disorder

Altered glial function, and increased proinflammatory cytokines are associated with behavioral and cognitive problems seen in autism spectrum disorder (ASD). In this study, we aimed to investigate the neuroinflammatory process in ASD and the relationship between neuroinflammatory markers and the severity of autism symptoms.

We evaluated the gene expression levels of NLRP-3 and RANK-RANKL-OPG inflammasome pathways in 50 children with ASD (AC), 34 typically developing siblings (HSAC), and 16 healthy controls (HC) and the correlation between gene expression levels and severity of neuro-psychiatric dysfunctions in ASD. All children were aged 3-18 years. The severity of autism core symptoms and neurologic dysfunction was determined by the Childhood Autism Rating Scale (CARS), Turkish Communication Development Inventory (TCDI), Dunn's Sensory Profile, Adolescents/Adults Sensory Profile and Clinical Observation of Neuromotor Performance, and the scores were correlated with gene expression levels.

Up-regulation was observed in all genes (IL-1β, Casp1, NLRP3, NLRP1, TNFRSF11B, TNFRSF11A, and TNFSF11) in the ASD group, but only the difference between the AC and HC groups was statistically significant for TNFRSF11B, TNFRSF11A, and TNFSF11. There were significant correlations in the linguistic and cognitive skills, sensory profile, and neuromotor performance domains for genes associated with both inflammatory pathways.

This is the first study showing that the RANK-RANKL-OPG pathway is active in ASD cases. Our results emphasize the harmful influence of the RANK-RANKL-OPG and NLRP3 inflammasome complexes on neurologic development.