mtDNA-cGAS-STING axis-dependent NLRP3 inflammasome activation contributes to postoperative cognitive dysfunction induced by sevoflurane in mice

Abstract

Abstract Background NLRP3 inflammasome activation is critical for neuroinflammation in microglia during postoperative cognitive dysfunction (POCD) induced by sevoflurane. However, the molecular mechanism by which sevoflurane activates the NLRP3 inflammasome in microglia remains unclear. The cGAS- STING pathway is an evolutionarily conserved inflammatory defense mechanism. The role of the cGAS-STING pathway in sevoflurane-induced NLRP3 inflammasome-dependent neuroinflammation and the underlying mechanisms require further investigation. Methods Prolonged anesthesia with sevoflurane was used to induce cognitive dysfunction in mice. The passive avoidance test and Y-maze test were used to assess cognitive function. We then used the cGAS inhibitor RU.521 to investigate whether the cGAS-STING pathway was involved in the NLRP3 inflammasome activation in sevoflurane-induced cognitive dysfunction in mice and neuroinflammation in microglia. To investigate the mechanism of cGAS-STING pathway activation in sevoflurane-treated microglia, we pre-treated microglia with Mdivi-1 (a DRP1 inhibitor), CsA (a mPTP inhibitor) or VBIT-4 (a VDAC inhibitor). Results We found that prolonged anesthesia with sevoflurane induced cognitive dysfunction and triggered the neuroinflammation characterized by the activation of NLRP3 inflammasome. Interestingly, the cGAS-STING pathway was activated in the hippocampus of mice receiving sevoflurane. While the blockade of cGAS with RU.521 attenuated cognitive dysfunction and NLRP3 inflammasome activation in mice. In vitro, we found that sevoflurane treatment significantly activated the cGAS-STING pathway in microglia, while RU.521 pre-treatment robustly inhibited sevoflurane-induced NLRP3 inflammasome activation. Mechanistically, sevoflurane-induced mitochondrial fission in microglia and released mitochondrial DNA (mtDNA) into the cytoplasm, which could be abolished with Mdivi-1. Blocking the mtDNA release via the mPTP-VDAC channel attenuated sevoflurane-induced mtDNA cytosolic escape and reduced cGAS-STING pathway activation in microglia, finally inhibiting the NLRP3 inflammasome activation. Conclusion In this study, we reported that the cGAS-STING pathway is a novel mechanism of NLRP3 inflammasome activation induced by sevoflurane in microglia during POCD. Therefore, regulating neuroinflammation by targeting the cGAS-STING pathway may provide a novel therapeutic target for POCD.