Jul 2026· Journal of Translational Medicine· 0 citations
Medicine
TL;DR
Altered RAGE signaling is the proposed mechanistic link between ongoing inflammation and impaired oxytocinergic signaling contributing to ASD pathogenesis in certain subgroups.
Abstract
Background
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.
MAIN BODY
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.
Conclusion
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.
Autism spectrum disorder (ASD) is characterized by persistent impairments in social communication together with restricted and repetitive patterns of behavior. Although ASD has traditionally been viewed primarily as a disorder of neural circuitry, increasing evidence indicates that interactions between the immune and nervous systems contribute substantially to brain development and cognitive function. This review develops a neuroimmune–cognitive–account of ASD by examining how immune signaling may influence neural organization and, in turn, cognitive function. Evidence from neuroimmunology, systems neuroscience, and experimental studies of neuromodulation is synthesized to examine relationships among immune signaling, neural network organization, and cognition. Disturbances in these processes have been associated with alterations in excitation–inhibition –balance and atypical large-scale connectivity, especially within networks supporting social cognition. We also examine the role of neuromodulatory systems, with particular emphasis on oxytocin and vasopressin, as intermediaries between biological regulation and cognitive processing. Experimental findings indicate that oxytocin can transiently modulate activity within social brain networks and increase the salience of socially relevant stimuli, although effects across clinical studies remain modest and inconsistent. The reviewed evidence suggests that disturbances in neuroimmune regulation may contribute to altered communication among distributed neural systems, providing one possible account of cognitive dysfunction in ASD. Social deficits, repetitive behaviors, and sensory differences reflect disturbances in the coordination of distributed neural systems rather than isolated impairments within single regions or pathways. This view has important implications for intervention, suggesting that approaches directed at individual molecular or neural targets alone are unlikely to produce broad or lasting effects. More effective strategies may require interventions that address interactions among immune function, neural dynamics, and cognitive processes. The resulting neuroimmune–cognitive account generates testable hypotheses concerning how immune processes may influence neural organization and cognition in ASD while providing a conceptual basis for future experimental and clinical research.
Sherif Ganem, Gerry Leisman, R. Melillo· International Journal of Cog...· 0 citations
Chronic stress and inflammation are potent determinants of negative health trajectories across adulthood, contributing to the progression of neurodegenerative diseases. In aging, these processes become increasingly intertwined, forming a feedforward loop in which chronic stress activates pro-inflammatory cascades in the brain and body, while pro-inflammatory cytokines stimulate stress-response pathways. Together, these interactions accelerate neuronal vulnerability, cognitive decline, and even Alzheimer's disease and Related Dementia (ADRD) pathology. The neuropeptide oxytocin (OT), a modulator of neurophysiological and social-affiliative processes, may buffer against stress and inflammation. There is evidence suggesting that OT dampens hypothalamic-pituitary-adrenal (HPA) axis reactivity, reduces pro-inflammatory cytokines, and promotes adaptive behaviors that restore physiological balance and promote healthy coping. OT can be synthetically produced and delivered via intranasal administration (IN-OT), providing a potential means of enhancing OT signaling. Understanding OT's role in aging, however, remains limited but of high relevance, also given the convergence of stress and inflammatory cascades in ADRD. This narrative review integrates previously distinct lines of research to delineate proposed pathways through which OT regulates stress and inflammation in aging and ADRD. Using systematic search strategies, this review also provides a structured synthesis of recent studies to evaluate evidence for IN-OT as a therapeutic for mitigating stress and inflammation, with discussion of its potential application in aging and ADRD. Research gaps and future directions are offered regarding OT's mechanisms of action, moderators of IN-OT's treatment response, and enhanced attention to midlife in IN-OT research on stress and inflammation in older adults as well as individuals with ADRD.
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Integrative pathogenetic mechanisms of ASD are explored, encompassing prenatal viral exposure, alterations in serotonin and oxytocin signaling pathways, regulation of N-methyl-D-aspartate receptors, SHANK proteins, and members of the Solute Carrier protein family.
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