P2X7 Signaling in Neuroinflammation: Glial Crosstalk, Redox Integration, and Therapeutic Targeting

Extracellular ATP is a central danger signal linking cellular stress to neuroinflammation, yet the mechanisms governing the transition from physiological purinergic signaling to pathological neuroimmune activation remain incompletely understood. In this review, we integrate current evidence into a conceptual framework describing how ATP-dependent purinergic signaling may contribute to the shift from adaptive neuron-glia communication to maladaptive glial crosstalk and inflammatory amplification. Under physiological conditions, controlled ATP turnover primarily engages lower-threshold purinergic pathways, including P2X4-mediated signaling that supports microglial surveillance, synaptic remodeling, and tissue homeostasis. In contrast, sustained extracellular ATP accumulation during injury, oxidative stress, or impaired ATP clearance preferentially recruits the low-affinity P2X7 receptor, triggering ionic dysregulation, Ca²⁺ influx, and redox-sensitive signaling pathways that promote NF-κB activation and NLRP3 inflammasome assembly. We further examine how receptor crosstalk, particularly with TLR4 and emerging redox regulatory mechanisms involving protein disulfide isomerase (PDI), may influence P2X7 signaling across different neuroinflammatory contexts. Finally, we discuss current evidence for therapeutic targeting of P2X7, highlighting translational challenges related to blood-brain barrier penetration, receptor occupancy, disease stage, and patient selection. By integrating recent advances in purinergic, redox, and neuroimmune signaling, this review provides a heuristic framework for understanding context-dependent P2X7 activation while distinguishing established mechanisms from emerging concepts that require further experimental validation.