Brain–Spleen Axis in Psychosocial Stress-Related Inflammatory Diseases: Mechanisms and Therapeutic Perspectives

Psychosocial stress is a significant trigger for various somatic inflammatory diseases. Building on classical evidence that sympathetic nerves innervate lymphoid organs and that a vagally initiated inflammatory reflex restrains splenic cytokine production, recent work has delineated a brain–spleen axis, in which identified central neurons connect through peripheral nerves, rather than endocrine hormones, to the spleen to regulate innate and adaptive immunity. Dysfunction of this axis has been associated with the development and progression of several psychosocial stress-related inflammatory conditions. Therapeutic strategies that may engage the brain–spleen axis, including pharmacotherapy, physical neuromodulation, behavioral interventions, and traditional Chinese medicine, show preliminary promise, although for most of them a dependence on the spleen has not yet been directly demonstrated. This review summarizes recent advances on the anatomical basis, molecular mechanisms, disease relevance, and therapeutic targeting of the brain–spleen axis, distinguishing established findings from working hypotheses, with the aim of informing precision prevention and treatment strategies for psychosocial stress-related inflammatory diseases.