Mitochondrial DNA from endothelial cells activated the cGAS-STING pathway and regulated pyroptosis in lung ischaemia reperfusion injury after lung transplantation
Objective: Cell dysfunction and death induced by lung ischaemia–reperfusion injury (LIRI) are the main causes of death in transplant patients. Activation of the cGAS-STING-induced immune response and death plays a critical role in multiple organ injuries. However, no study has yet investigated the r...
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Elsevier
2025-01-01
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| Series: | Immunobiology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0171298524000834 |
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| author | Ying-nan Ju Hu Li Zi-peng Zhuo Qing Yang Wei Gao |
| author_facet | Ying-nan Ju Hu Li Zi-peng Zhuo Qing Yang Wei Gao |
| author_sort | Ying-nan Ju |
| collection | DOAJ |
| description | Objective: Cell dysfunction and death induced by lung ischaemia–reperfusion injury (LIRI) are the main causes of death in transplant patients. Activation of the cGAS-STING-induced immune response and death plays a critical role in multiple organ injuries. However, no study has yet investigated the role of the cGAS-STING pathway in LIRI after lung transplantation. Methods: Sprague-Dawley (SD) rats were subjected to left lung transplantation and administered inhibitors of cGAS and STING. The expression of cGAS-STING-TBK1-IRF3, histological injury, pulmonary permeability, and the levels of cytokines and pyroptotic proteins in transplanted lungs were tested. Endothelial cells were subjected to hypoxemia and reoxygenation and treated with inhibitors of cGAS and STING. Mitochondrial DNA (mtDNA), the cGAS-STING axis and cytokine levels in cells, cellular activity and death were evaluated. Moreover, after the administration of deoxyribonuclease (DNase) I, the reoxygenated endothelial cells were also examined for cellular function and inflammatory factor expression. Finally, we administered an agonist of STING and an inhibitor of cathepsin B to the normal endothelium and investigated pyroptosis and pyroptotic proteins. Results: After 24 h of reperfusion, the expression of cGAS-STING-TBK1-IRF3 and pyroptotic proteins was significantly increased, and inhibitors of cGAS or STING ameliorated lung injury and reduced pyroptotic protein levels. In vitro, the inhibition of cGAS and STING reduced the activation of TBK and IRF3 and reduced cellular injury and death. The activation of cGAS-STING and cellular inflammation were suppressed by DNase I. Cathepsin B and NLRP3 were upregulated by an agonist of STING, and an inhibitor of cathepsin B reduced NLRP3 levels. Conclusion: cGAS-STING participated in LIRI by promoting endothelial cell pyroptosis via cathepsin B. |
| format | Article |
| id | doaj-art-c97f1da803c04e6fb0ac96acb3d9863e |
| institution | Kabale University |
| issn | 0171-2985 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Immunobiology |
| spelling | doaj-art-c97f1da803c04e6fb0ac96acb3d9863e2025-01-27T04:21:42ZengElsevierImmunobiology0171-29852025-01-012301152865Mitochondrial DNA from endothelial cells activated the cGAS-STING pathway and regulated pyroptosis in lung ischaemia reperfusion injury after lung transplantationYing-nan Ju0Hu Li1Zi-peng Zhuo2Qing Yang3Wei Gao4Department of Intensive Care Unit, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570 311, ChinaDepartment of Critical Care Medicine, Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150081, ChinaDepartment of Critical Care Medicine, Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150081, ChinaDepartment of Critical Care Medicine, Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150081, ChinaDepartment of Anesthesiology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570311, China; Corresponding author at: Department of Anesthesiology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570311, China.Objective: Cell dysfunction and death induced by lung ischaemia–reperfusion injury (LIRI) are the main causes of death in transplant patients. Activation of the cGAS-STING-induced immune response and death plays a critical role in multiple organ injuries. However, no study has yet investigated the role of the cGAS-STING pathway in LIRI after lung transplantation. Methods: Sprague-Dawley (SD) rats were subjected to left lung transplantation and administered inhibitors of cGAS and STING. The expression of cGAS-STING-TBK1-IRF3, histological injury, pulmonary permeability, and the levels of cytokines and pyroptotic proteins in transplanted lungs were tested. Endothelial cells were subjected to hypoxemia and reoxygenation and treated with inhibitors of cGAS and STING. Mitochondrial DNA (mtDNA), the cGAS-STING axis and cytokine levels in cells, cellular activity and death were evaluated. Moreover, after the administration of deoxyribonuclease (DNase) I, the reoxygenated endothelial cells were also examined for cellular function and inflammatory factor expression. Finally, we administered an agonist of STING and an inhibitor of cathepsin B to the normal endothelium and investigated pyroptosis and pyroptotic proteins. Results: After 24 h of reperfusion, the expression of cGAS-STING-TBK1-IRF3 and pyroptotic proteins was significantly increased, and inhibitors of cGAS or STING ameliorated lung injury and reduced pyroptotic protein levels. In vitro, the inhibition of cGAS and STING reduced the activation of TBK and IRF3 and reduced cellular injury and death. The activation of cGAS-STING and cellular inflammation were suppressed by DNase I. Cathepsin B and NLRP3 were upregulated by an agonist of STING, and an inhibitor of cathepsin B reduced NLRP3 levels. Conclusion: cGAS-STING participated in LIRI by promoting endothelial cell pyroptosis via cathepsin B.http://www.sciencedirect.com/science/article/pii/S0171298524000834cGAS-STINGLung ischemia reperfusion injuryLung transplantationPyroptosis |
| spellingShingle | Ying-nan Ju Hu Li Zi-peng Zhuo Qing Yang Wei Gao Mitochondrial DNA from endothelial cells activated the cGAS-STING pathway and regulated pyroptosis in lung ischaemia reperfusion injury after lung transplantation Immunobiology cGAS-STING Lung ischemia reperfusion injury Lung transplantation Pyroptosis |
| title | Mitochondrial DNA from endothelial cells activated the cGAS-STING pathway and regulated pyroptosis in lung ischaemia reperfusion injury after lung transplantation |
| title_full | Mitochondrial DNA from endothelial cells activated the cGAS-STING pathway and regulated pyroptosis in lung ischaemia reperfusion injury after lung transplantation |
| title_fullStr | Mitochondrial DNA from endothelial cells activated the cGAS-STING pathway and regulated pyroptosis in lung ischaemia reperfusion injury after lung transplantation |
| title_full_unstemmed | Mitochondrial DNA from endothelial cells activated the cGAS-STING pathway and regulated pyroptosis in lung ischaemia reperfusion injury after lung transplantation |
| title_short | Mitochondrial DNA from endothelial cells activated the cGAS-STING pathway and regulated pyroptosis in lung ischaemia reperfusion injury after lung transplantation |
| title_sort | mitochondrial dna from endothelial cells activated the cgas sting pathway and regulated pyroptosis in lung ischaemia reperfusion injury after lung transplantation |
| topic | cGAS-STING Lung ischemia reperfusion injury Lung transplantation Pyroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S0171298524000834 |
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