Mechanisms of Neuroimmune Interactions in Stress Physiology, Health Implications, and Emerging Therapeutic Targets.

Chronic stress provokes maladaptive neuroimmune responses that disrupt the balance between the central nervous system and immune regulation. Dysregulation of the hypothalamic pituitary adrenal (HPA) axis, sympathetic adrenal medullary (SAM) system, and peripheral immune circuits sustains microglial activation and pro-inflammatory cytokine release. The process is responsible for driving persistent neuroinflammation. These changes impair synaptic plasticity, compromise blood-brain barrier integrity, and predispose individuals to psychiatric illness, cognitive dysfunction, and systemic comorbidities. Recent advances reveal key molecular mechanisms, including glucocorticoid receptor resistance, epigenetic reprogramming, and cytokine-neurotransmitter cross-talk that explain how stress reshapes brain-immune communication. This review critically examines the evidence linking chronic stress to neuroimmune dysfunction, emphasizing both translational challenges and therapeutic opportunities. Emerging interventions such as cytokine blockade, microglial modulation, specialized pro-resolving mediators, neurosteroids, and microbiome-based strategies highlight the potential of mechanism-based treatments. However, clinical translation is hampered by heterogeneity in inflammatory phenotypes, limited biomarker validation, and insufficient longitudinal data. Future research must prioritize precision medicine approaches that integrate multi-omics profiling, sex- and hormone-specific analyses, and digital biosensing tools. By bridging neuroscience, immunology, and systems biology, targeted strategies can be developed to prevent and treat stress-related disorders more effectively.