Peripheral inflammasome activity and domain-specific behavioural associations in preschool children with autism spectrum disorder

Peripheral innate immune activation and inflammasome signalling have been implicated in the pathophysiology of autism spectrum disorder (ASD), although findings remain inconsistent across studies in the existing literature. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome regulates the maturation of pro-inflammatory cytokines such as interleukin (IL)-1β and IL-18 and may play a role in neurodevelopmental processes. This study aimed to investigate serum levels of NLRP3-related inflammatory markers and systemic inflammation indices in preschool children with ASD and to examine their associations with behavioural domains and symptom dimensions.

This cross-sectional study included 44 children aged 2–6 years diagnosed with ASD and 44 age- and sex-matched healthy controls. All children underwent psychiatric evaluations according to DSM-5 criteria; developmental levels and adaptive functioning were assessed using the Vineland Adaptive Behavior Scales (Vineland-II). In the ASD group, symptom severity was evaluated using the Childhood Autism Rating Scale (CARS), Autism Behavior Checklist (ABC), Strengths and Difficulties Questionnaire (SDQ; 2–4 years), and Repetitive Behavior Scale–Revised (RBS-R; Turkish version). Serum levels of NLRP3, caspase-1, IL-1β, IL-18, P2X7 receptor (P2X7R), NIMA-related kinase 7 (NEK7), and C-reactive protein were measured using enzyme-linked immunosorbent assay methods. Inflammation indices, including neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and systemic immune-inflammation index, were calculated from complete blood count parameters. Statistical analyses were performed using R. Normality was assessed with the Shapiro–Wilk test. Between-group comparisons were conducted using the Mann–Whitney U test, chi-square test, or Fisher’s exact test as appropriate. Correlations were analysed using Spearman’s rank correlation coefficient, with a two-tailed significance threshold of p<0.05.

No significant between-group differences were observed in serum levels of NLRP3, caspase-1, IL-1β, IL-18, P2X7 receptor, NEK7, C-reactive protein, or hematological inflammation indices (all p>0.05). Within the ASD group, multiple weak-to-moderate, domain-specific correlations were observed between inflammatory markers and behavioural domains. NLRP3-related markers showed positive correlations with social interaction and imitation domains of the Childhood Autism Rating Scale. All NLRP3-related inflammatory parameters were negatively correlated with the total and subscale scores of the Repetitive Behavior Scale–Revised (RBS-R; Turkish version), including “insistence on sameness” and “self-injurious behaviours”. Negative correlations were also found between NLRP3-related markers and total difficulties scores on the Strengths and Difficulties Questionnaire. No significant associations were identified between inflammatory markers and developmental or adaptive functioning measures, and no significant relationships were observed in the control group.

Although peripheral NLRP3 inflammasome-related markers did not differ between groups, their consistent and domain-specific associations with behavioural phenotypes in ASD suggest that inflammasome-related pathways may interact with distinct symptom dimensions rather than reflecting a global disease marker. These findings support the concept of biological heterogeneity and fractionable phenotypes in ASD and highlight the importance of examining dimensional relationships between immune markers and specific clinical features across different symptom domains. Further longitudinal, mechanistic, and multi-level studies are needed to clarify causal pathways and their potential clinical relevance for targeted interventions in ASD.

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