The processing of pro-inflammatory cytokines in post-traumatic stress disorder: Inflammation as a central mechanism in PTSD pathophysiology.

Abstract

Post-traumatic stress disorder (PTSD) is a severe psychiatric condition associated with persistent emotional dysregulation, cognitive impairment, and structural alterations in limbic and prefrontal brain regions. Growing evidence indicates that chronic inflammation and abnormal processing of pro-inflammatory cytokines are central components of PTSD pathophysiology. Activation of the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) and caspase-1 promotes the proteolytic maturation of pro-interleukin-1β (pro-IL-1β) and pro-interleukin-18 (pro-IL-18) into their active forms, amplifying neuroinflammatory signaling. Sustained microglial activation and disrupted neuron-microglia-astrocyte communication contribute to synaptic dysfunction and impaired neuroplasticity. In parallel, dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis) interacts with inflammatory pathways, leading to altered stress responses and persistent immune activation. Clinical studies have demonstrated associations between circulating inflammatory mediators, including IL-18 and IL-1β, and the severity of emotional inhibition, sleep disturbances, and maladaptive coping strategies in PTSD. Moreover, inflammatory activity has been linked to volumetric and microstructural changes in the hippocampus, amygdala, and prefrontal cortex observed in chronic PTSD. These findings support the concept that the processing of pro-inflammatory cytokines is a central mechanism in PTSD rather than a secondary consequence of stress exposure. Understanding the molecular pathways underlying cytokine maturation and neuroimmune signaling may contribute to improved biomarker-based diagnostics and the development of targeted therapeutic interventions.