Oxytocin and RAGE Signaling Link Neurodevelopmental Inflammation to Autism Spectrum Disorder Pathophysiology

Autism Spectrum Disorder (ASD) prevalence continues to rise, yet its underlying pathophysiology remains largely elusive. A significant body of evidence points to gestational and postnatal inflammation as a strong correlate, supported by studies on maternal immune activation and altered T-cell populations in affected children. Subgroups of ASD children exhibit elevated inflammatory markers like TNF-α, interleukins, nuclear factors, and toll-like receptor levels, suggesting a chronic inflammatory process. This cellular danger response is posited to impact immune cells, contributing to the complex ASD phenotype.

This review synthesizes current literature exploring the intricate relationship between Autism Spectrum Disorder (ASD), inflammation, and the RAGE (Receptor for Advanced Glycation Endproducts) system, with a specific focus on its interaction with oxytocin (OXT) signaling. Researchers examined evidence from maternal immune activation studies, immunological markers in ASD children, and preclinical models to build a comprehensive model linking early inflammatory insults to the autistic phenotype. The paper integrates findings on RAGE's role in inflammatory gene expression, biomolecule transport, and immune cell function, particularly concerning OXT.

The RAGE system, a multi-ligand receptor within the immunoglobulin superfamily, plays a critical role in inflammatory gene signaling, potentially explaining how early prenatal and ongoing inflammatory insults contribute to the autistic phenotype. ASD patients exhibit distinct differences in RAGE signaling, including elevations in inflammatory gene expression ligands such as AGEs, HMGB1, and the S100 family. Concurrently, decreases in esRAGE, regionally altered C1q, and impaired APP metabolism are observed. These ligands are crucial for increasing inflammatory gene expression, modulating biomolecule transport, or mediating immune cell migration and phagocytosis. > The RAGE system has also been demonstrated to be involved in gut-blood and blood-brain oxytocin transport, with chronic inflammation in mouse models associated with impaired oxytocin transport across these barriers. Young children with ASD consistently show lower serum oxytocin levels compared to age-matched controls, and these serum OXT levels significantly correlate with social communication testing scores across all groups of children. Furthermore, ASD patients frequently present with increased prevalence of inflammatory conditions like asthma, atopic dermatitis, allergic rhinitis, and irritable bowel syndrome, indicating ongoing inflammatory hyperactivity in certain subgroups that may disrupt OXT signaling.