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mtDNA-cGAS-STING axis-dependent NLRP3 inflammasome activation contributes to postoperative cognitive dysfunction
Nan-Shi-Yu Yang1,2,3, Wen-Jing Zhong1,2,3, Han-Xi Sha1,2,3
1Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China.
Abstract:
The activation of NLRP3 inflammasome in microglia is critical for neuroinflammation 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. We found that prolonged anesthesia with sevoflurane induced cognitive dysfunction and triggered the neuroinflammation characterized by the activation of NLRP3 inflammasome in vivo. 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 inhibitor attenuated sevoflurane-induced mtDNA cytosolic escape and reduced cGAS-STING pathway activation in microglia, finally inhibiting the NLRP3 inflammasome activation. Therefore, regulating neuroinflammation by targeting the cGAS-STING pathway may provide a novel therapeutic target for POCD.
Insights
Sevoflurane anesthesia triggers neuroinflammation and cognitive dysfunction by activating the cGAS-STING pathway in microglia. Blocking this pathway with RU.521 reduces inflammation and cognitive deficits, offering a potential therapeutic target for postoperative cognitive dysfunction (POCD).
Area of Science:
- Neuroscience
- Immunology
- Anesthesiology
Background:
- Postoperative cognitive dysfunction (POCD) is linked to neuroinflammation mediated by the NLRP3 inflammasome in microglia.
- The precise mechanism of sevoflurane-induced NLRP3 inflammasome activation in microglia remains largely unknown.
- The cGAS-STING pathway is a key inflammatory defense mechanism requiring further investigation in sevoflurane-induced neuroinflammation.
Purpose of the Study:
- To elucidate the role of the cGAS-STING pathway in sevoflurane-induced NLRP3 inflammasome-dependent neuroinflammation and POCD.
- To investigate the underlying molecular mechanisms connecting sevoflurane anesthesia to microglial activation and cognitive impairment.
Main Methods:
- In vivo studies in mice subjected to prolonged sevoflurane anesthesia.
- In vitro experiments using microglial cell cultures treated with sevoflurane.
- Pharmacological blockade of the cGAS-STING pathway using RU.521 and mitochondrial fission inhibitor Mdivi-1.
- Assessment of cognitive function, neuroinflammation markers, NLRP3 inflammasome activation, cGAS-STING pathway signaling, and mitochondrial DNA release.
Main Results:
- Sevoflurane anesthesia induced cognitive dysfunction and neuroinflammation, marked by NLRP3 inflammasome activation in vivo.
- The cGAS-STING pathway was activated in the hippocampus following sevoflurane exposure, and its blockade with RU.521 ameliorated cognitive deficits and neuroinflammation.
- In vitro, sevoflurane activated the cGAS-STING pathway in microglia, leading to NLRP3 inflammasome activation, which was inhibited by RU.521.
- Sevoflurane induced mitochondrial fission and subsequent mitochondrial DNA (mtDNA) release into the cytoplasm, activating the cGAS-STING pathway.
- Inhibition of mtDNA release via mPTP-VDAC channel blockers attenuated cGAS-STING and NLRP3 inflammasome activation.
Conclusions:
- The cGAS-STING pathway mediates sevoflurane-induced neuroinflammation and cognitive dysfunction in POCD.
- Sevoflurane triggers this pathway through mitochondrial fission and subsequent mtDNA release from microglia.
- Targeting the cGAS-STING pathway presents a promising therapeutic strategy for mitigating sevoflurane-induced POCD.
