Chronic Social Stress and Immune Dysregulation: Integrating Neuroendocrine Signaling, Microbiota, and Tissue-Specific Responses

Psychological stress arises when individuals perceive demands as exceeding their capacity to cope. Social stress can be acute, such as giving a presentation, producing transient increases in heart rate, blood pressure, and neuroendocrine activation, or chronic, in which stressors persist over extended periods. Chronic psychosocial stress disrupts immune homeostasis and contributes to anxiety, depression, and post-traumatic stress, while also increasing risk for infections, inflammatory and autoimmune diseases, cardiovascular disease, metabolic dysfunction, and cancer. Persistent stress engages interconnected neuroendocrine–immune networks, including the hypothalamic–pituitary–adrenal axis, the sympathetic–adrenomedullary system, and the gut microbiota–brain–immune axis, leading to sustained glucocorticoid and catecholamine signaling, gut dysbiosis, impaired barrier integrity, and altered microbial metabolite profiles. In this review, we summarize the molecular and cellular mechanisms by which these axes remodel innate and adaptive immunity and shape disease susceptibility. Using social defeat and social isolation in mice as model systems, we highlight how chronic social stress reprograms immune responses in key tissues, including the lung, brain, and gut.