Oxytocin and RAGE signaling at the intersection of social neurodevelopment and inflammation

Autism spectrum disorder (ASD) prevalence continues to rise despite no recent changes to screening or diagnostic criteria. A complete understanding of the pathophysiology of ASD remains elusive. Gestational and postnatal inflammation correlate strongly with ASD prevalence, which is supported by maternal immune activation prevalence studies, maternal immunoglobulin found in fetal brains with ASD and altered T-cell populations in ASD children. Elevated TNF-α, interleukins, nuclear factors, and toll-like receptor levels reported in subgroups of ASD children provide evidence of a chronic inflammatory process posited to be a consequence of a cellular danger response impacting T-cells, neutrophils, macrophages, and microglia.

The RAGE system is a multi-ligand receptor within the immunoglobulin (Ig) superfamily that plays a role in inflammatory gene signaling and may help explain how early prenatal and ongoing inflammatory insults are linked to the autistic phenotype. ASD patients demonstrate differences in RAGE signaling; elevations in inflammatory gene expression ligands (AGEs, HMGB1, S100 family), decreases in esRAGE, regionally altered C1q, and impaired APP metabolism. Each of these ligands serves a role as either increasing inflammatory gene expression, modulating transport of biomolecules, or mediating immune cell migration and phagocytosis. Additionally, the RAGE system has been demonstrated to be involved in gut-blood and blood-brain oxytocin transport. In the mouse model, chronic inflammation is associated with impaired oxytocin transport across these barriers. Young children with ASD have lower serum oxytocin levels than age-matched controls, and serum OXT levels correlate with social communication testing across all groups of children. ASD patients have an increased prevalence of asthma, atopic dermatitis, allergic rhinitis, and irritable bowel syndrome, indicating an ongoing inflammatory hyperactivity in some ASD subgroups that may disturb oxytocin transport, predisposing ASD symptomology. Furthermore, the gut microbiome and its metabolites influence RAGE signaling and may partially explain the differences in microbiome composition in ASD patients.

Altered RAGE signaling is the proposed mechanistic link between ongoing inflammation and impaired oxytocinergic signaling contributing to ASD pathogenesis in certain subgroups. Further research into the biomarkers involved could identify subpopulations of ASD patients that would benefit from early modulation of the RAGE system.