NLRP3 Inflammasome in Stress-Related Neuropsychiatric Disorders: Mechanisms of Neuron–Microglia–Astrocyte Crosstalk, HPA Axis Dysregulation, and Therapeutic Perspective

Chronic stress disrupts neuroimmune homeostasis and initiates CNS inflammation. This paper examines the molecular and cellular mechanisms that connect stress to the interplay among the nervous, endocrine, and immune systems, with a focus on the role of the NLRP3 inflammasome in neuroinflammatory processes. It discusses the dynamics of HPA axis, stress-induced changes in glucocorticoid and mineralocorticoid signaling, sympathetic nervous system activation, and the contribution of pro-inflammatory cytokines in brain immune activation. The NLRP3 inflammasome is described in terms of its structure, activation via a two-signal model, and its role in IL-1β and IL-18 maturation in neurons, microglia, and astrocytes. Preclinical evidence highlights the therapeutic potential of targeting NLRP3 in stress-related disorders, underscoring its key role in their pathophysiology.