Brain-organ axis: How does stress regulate peripheral immunity through neural signaling?

Abstract

External stimuli elicit behavioral responses through neural circuits, and growing evidence demonstrates that this regulatory process is closely associated with the immune system. The complex interplay between stress and immunity, as highlighted by recent interdisciplinary studies, is central to this relationship, highlighting the bidirectional communication between the nervous system and multiple peripheral organ systems. To better elucidate how the brain responds to external stressors, we propose the concept of the “brain–organ axis.” Analogous to coordinated teamwork, this framework emphasizes the synergistic interactions between the brain and peripheral organs. Under psychological stress, activation of the hypothalamic–pituitary–adrenal axis and sympathetic nervous system modulates the peripheral immunity in an organ-specific manner. Neurotransmitters, neuropeptides, and glucocorticoids collectively demonstrate that stress exerts differential effects on immune cell populations and local tissue microenvironments, particularly in the skin, gut, liver, heart, spleen, and lungs. These alterations promote the release of proinflammatory mediators, modify the immune surveillance states, and increase the susceptibility to infection. Conversely, peripheral inflammation affects central nervous system function via vagal afferent pathways and circulating cytokines, thereby forming a closed neuroimmune regulatory loop. This review integrates the recent findings on the brain–organ axis in the context of stress and psychological disorders from a radiating network perspective. Based on the neuroimmune interaction mechanisms, it explores how stress-induced emotional states achieve organ-specific regulation of local immune environments through a targeted modulation of neurotransmitters and immune cells, ultimately driving peripheral inflammation. By delineating stress-induced tissue-specific immune responses, this work clarifies the mechanisms through which psychological states influence somatic disease and provides a comprehensive overview of the role of psychological factors in systemic immunity.