Publication date: Jul 03, 2025
Psychological stress plays a critical role in the onset of depression by activating neuroimmune and endocrine responses, leading to dysregulation of the hypothalamic-pituitary-adrenal axis and increased inflammation. This imbalance impacts key brain regions involved in mood regulation, such as the prefrontal cortex, hippocampus, and amygdala, contributing to the development of depressive symptoms. Moreover, stress induces immune dysregulation and inflammation in peripheral organs, including the gut, spleen, liver, lungs, and heart, which can result in metabolic disorders, cardiovascular disease, and immune dysfunction. Chronic stress also disrupts gut microbiota and alters the gut-brain axis via the vagus nerve, further exacerbating stress-related mental health issues. The cumulative effect of stress on peripheral organs significantly impacts both physical and mental health, linking systemic dysfunction to depression. This comprehensive review delves into the intricate mechanisms by which the immune system regulates mood and explores the etiological factors underlying dysregulated inflammatory responses in depression. We also summarize the connections between the brain and peripheral organs-bone marrow, spleen, gut, adipose tissue, heart, liver, lungs, and muscles-highlighting their coordinated regulation of immune function in response to psychological stress. Additionally, we investigate specific brain regions and neuronal populations that respond to stress stimuli, transmitting signals through autonomic and neuroendocrine pathways to modulate immune function. Finally, we discuss emerging therapeutic strategies that leverage the interaction between endocrine signaling and inflammatory responses for the effective treatment of depression.