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

Abstract 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.