Neuroimmune Interactions in Stress and Depression: Exploring the Molecular and Cellular Mechanisms within the Neuroinflammation-depression Nexus

Background: The escalating global burden of stress and depression underscores an urgent need to unravel their complex interrelationships and underlying mechanisms. This investigation delves into the intricate dynamics between stress and depression, spotlighting the Neuroimmunoinflammatory Stress Model (NIIS), which elucidates the pivotal role of cellular and molecular pathways in mediating these conditions. Methods: Through an exhaustive review of literature spanning epidemiology, neurobiology, and psychoneuroimmunology, this study synthesizes the current understanding of stress and depression. It accentuates the definitional scopes, interplay, and intricacies of the NIIS model, which integrates neuroimmune-inflammatory responses into the conceptual framework of the stress-depression interaction. Results: By identifying stress as a multifactorial reaction to perceived adversities and depression as a manifestation of prolonged stress exposure, our analysis foregrounds the NIIS model. This paradigmatic model reveals the transition from normal stress responses to pathological neuroinflammatory pathways, highlighting neurotransmitter imbalances, disruptions in neuronal and glial homeostasis, and ensuing low-grade neuroinflammation as key factors in the pathogenesis of depression under chronic stress conditions. The NIIS model identifies prolonged cellular pro-inflammatory stress of neurons and microglia as a fundamental pathological subsystem of many neuropsychiatric disorders. In turn, neuroinflammation and associated neurodegenerative processes are complications of chronic psychoemotional stress, which can clinically manifest as depression. Conclusions: The NIIS model views depression as the terminal stage of chronic stress, pathogenetically linked to latent neuroinflammation. This insight not only advances our understanding of their etiopathogenesis but also paves the way for developing precise therapeutic interventions.