Oxytocin‐Mediate Modulation of Splenic Immunosuppression in Chronic Social Stress Through Neuroendocrine Pathways

Chronic social stress (CSS) is a significant public health challenge that negatively impacts behavior and immune function through brain-spleen interactions. Oxytocin (OT), a neuropeptide critical for social behavior and immune regulation, is upregulated during CSS, though its underlying mechanisms remain unclear. This study investigates the role of OT in splenic immune modulation using a murine model of CSS. Behavioral evaluations, serum oxytocin quantification, and splenic immunophenotypic analysis were performed. Splenic denervation confirmed OT's neuromodulatory role, whereas OTR antagonism revealed its endocrine function. CSS-induced OT elevation was associated with immunosuppression, characterized by increased Foxp3⁺ regulatory T cells and reduced CD4⁺ T and CD19⁺ B cells. OT also modulated macrophage polarization, inhibiting M1-like (pro-inflammatory) and enhancing M2-like (anti-inflammatory) phenotypes. Denervation or pharmacological blockade of OT signaling partly reversed CSS-induced splenic immunosuppression but adversely affected survival in CSS-exposed mice. Additionally, denervation or OTR antagonism reduced the mice's response to social defeat, as shown by decreased social avoidance behavior. These findings suggest that OT-mediated immunosuppression likely represents a compensatory mechanism in response to chronic social stress. Targeting the OT-immune axis could offer innovative therapeutic approaches for stress-associated disorders by restoring immune homeostasis while maintaining behavioral integrity.