An ATP-Linked Neuroimmune Pathway in Trauma: A Mechanistic Hypothesis Integrating Mitochondrial Stress and Developmental Vulnerability

Psychological trauma is associated with diverse psychiatric and somatic outcomes; however, the biological mechanisms underlying this heterogeneity remain unclear. Emerging evidence suggests that mitochondrial stress and extracellular adenosine triphosphate (ATP) release may contribute to sustained neuroimmune activation in a subset of trauma responses. These ATP-linked pathways intersect with established stress-biology mechanisms, including the hypothalamic-pituitary-adrenal axis dynamics, glucocorticoid signaling, and inflammatory cytokine cascades. Developmental timing, particularly during the preverbal period, may further shape long-term neuroimmune sensitivity owing to immature antioxidant defenses and heightened glial plasticity. A structured search identified 19 studies that examine trauma regarding mitochondrial dysfunction, ATP signaling, inflammasome activation, and related neuroimmune mechanisms. Findings were synthesized narratively at the receptor level. In preclinical and clinical studies, trauma exposure has been associated with mitochondrial stress, extracellular ATP efflux, P2X7 receptor activation, and NLRP3 inflammasome assembly. These processes were amplified by cGAS–STING signaling and sustained through TLR4 and the receptor for advanced glycation end products (RAGE) engagement. Early-life adversity has been consistently linked to increased inflammatory reactivity. These findings support a conceptual continuum model in which ATP-mediated neuroinflammation represents a hypothetical mechanistic pathway contributing to trauma chronicity. This framework complements existing models by offering receptor-level specificity and highlighting avenues for biomarker development and targeted intervention research.