Abstract

Although chronic stress is known to trigger neuroinflammation and depressive-like behaviors, the mechanisms linking stress sensors to inflammatory cascades remain elusive. The purinergic receptor P2X7 (P2X7R), an extracellular ATP-gated cation channel primarily expressed in microglia, is a critical link between stress and neuroinflammation. While the cGAS-STING signaling pathway has been implicated in microglial reactivity, it remains unknown whether P2X7R signals via this pathway. Here, we demonstrate that chronic restraint stress in mice activates microglial P2X7R in the hippocampus, inducing mitochondrial damage. This was accompanied by activation of the cGAS-STING pathway, elevating phosphorylated STING and IRF3 levels along with pro-inflammatory cytokines. Pharmacological inhibition of P2X7R (JNJ-47965567) or STING (H-151) attenuated neuroinflammation and alleviated depressive-like behaviors. In vitro, LPS-stimulated BV2 microglia exhibited mtDNA release and cGAS-STING activation. P2X7R knockdown or pharmacological inhibition attenuated mitochondrial dysfunction, mtDNA release, and subsequent phosphorylation of STING and IRF3. In conclusion, our findings unveil a previously unrecognized mechanism in the neuroimmunological pathology of depressive-like behaviors, demonstrating that chronic stress triggers neuroinflammation through a microglial pathway involving P2X7R-mediated mitochondrial damage, mtDNA release, and cGAS-STING activation. Graphical