Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB Pathway
BackgroundIn animal models of ventilation-induced lung injury, mitophagy triggers mitochondria damage and the release of mitochondrial (mt) DNA, which activates inflammation. However, the mechanism of this process is unclear.MethodsA model of cyclic stretching (CS)-induced lung epithelial cell injur...
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Frontiers Media S.A.
2020-09-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2020.00819/full |
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| author | Ren Jing Ren Jing Zhao-Kun Hu Zhao-Kun Hu Fei Lin Fei Lin Sheng He Sheng He Sui-Sui Zhang Sui-Sui Zhang Wan-Yun Ge Wan-Yun Ge Hui-jun Dai Hui-jun Dai Xue-Ke Du Xue-Ke Du Jin-Yuan Lin Jin-Yuan Lin Ling-Hui Pan Ling-Hui Pan |
| author_facet | Ren Jing Ren Jing Zhao-Kun Hu Zhao-Kun Hu Fei Lin Fei Lin Sheng He Sheng He Sui-Sui Zhang Sui-Sui Zhang Wan-Yun Ge Wan-Yun Ge Hui-jun Dai Hui-jun Dai Xue-Ke Du Xue-Ke Du Jin-Yuan Lin Jin-Yuan Lin Ling-Hui Pan Ling-Hui Pan |
| author_sort | Ren Jing |
| collection | DOAJ |
| description | BackgroundIn animal models of ventilation-induced lung injury, mitophagy triggers mitochondria damage and the release of mitochondrial (mt) DNA, which activates inflammation. However, the mechanism of this process is unclear.MethodsA model of cyclic stretching (CS)-induced lung epithelial cell injury was established. The genetic intervention of phosphatase and tensin homolog-induced kinase 1 (PINK1) expression via lentivirus transfection was used to identify the relationship between PINK1-mediated mitophagy and mtDNA release in stretching-induced inflammatory response and injury. Pharmacological inhabitation of Toll-like receptor 9 (TLR9) and myeloid differentiation factor 88 (MyD88) expression was performed via their related inhibitors, while pre-treatment of exogenous mtDNA was used to verify the role of mtDNA in stretching-induced inflammatory response and injury.ResultsUsing a cell culture model of CS, we found that knocking down PINK1 in lung epithelial cells reduced mitophagy activation and mtDNA release, leading to milder inflammatory response and injury; conversely, up-regulating PINK1 exacerbated stretching-induced inflammation and injury, and similar effects were observed by upregulating TLR9 to induce expression of MyD88 and nuclear factor-κB (NF-κB)/p65. Down-regulating MyD88 protected lung epithelial cells from stretching injury and decreased NF-κB/p65 expression.ConclusionThese findings suggest that PINK1-dependent mitophagy and associated TLR9 activation is indeed a major factor in stretch-induced cell injury via a mechanism in which released mtDNA activates TLR9 and thereby the MyD88/NF-κB pathway. Inhibiting this process may be a therapeutic approach to prevent inflammation and cell injury in patients on mechanical ventilation. |
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| language | English |
| last_indexed | 2024-04-13T15:30:37Z |
| publishDate | 2020-09-01 |
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| spelling | doaj.art-036818f738534ec1bc0f32b59d4ee9752022-12-22T02:41:23ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-09-01810.3389/fcell.2020.00819568355Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB PathwayRen Jing0Ren Jing1Zhao-Kun Hu2Zhao-Kun Hu3Fei Lin4Fei Lin5Sheng He6Sheng He7Sui-Sui Zhang8Sui-Sui Zhang9Wan-Yun Ge10Wan-Yun Ge11Hui-jun Dai12Hui-jun Dai13Xue-Ke Du14Xue-Ke Du15Jin-Yuan Lin16Jin-Yuan Lin17Ling-Hui Pan18Ling-Hui Pan19Department of Anesthesiology, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaThe Laboratory of Perioperative Medicine Research Center, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaDepartment of Anesthesiology, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaThe Laboratory of Perioperative Medicine Research Center, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaDepartment of Anesthesiology, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaThe Laboratory of Perioperative Medicine Research Center, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaDepartment of Anesthesiology, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaThe Laboratory of Perioperative Medicine Research Center, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaDepartment of Anesthesiology, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaThe Laboratory of Perioperative Medicine Research Center, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaDepartment of Anesthesiology, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaThe Laboratory of Perioperative Medicine Research Center, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaDepartment of Anesthesiology, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaThe Laboratory of Perioperative Medicine Research Center, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaDepartment of Anesthesiology, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaThe Laboratory of Perioperative Medicine Research Center, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaDepartment of Anesthesiology, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaThe Laboratory of Perioperative Medicine Research Center, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaDepartment of Anesthesiology, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaThe Laboratory of Perioperative Medicine Research Center, Guangxi Medical University Affiliated Tumor Hospital & Oncology Medical College, Nanning, ChinaBackgroundIn animal models of ventilation-induced lung injury, mitophagy triggers mitochondria damage and the release of mitochondrial (mt) DNA, which activates inflammation. However, the mechanism of this process is unclear.MethodsA model of cyclic stretching (CS)-induced lung epithelial cell injury was established. The genetic intervention of phosphatase and tensin homolog-induced kinase 1 (PINK1) expression via lentivirus transfection was used to identify the relationship between PINK1-mediated mitophagy and mtDNA release in stretching-induced inflammatory response and injury. Pharmacological inhabitation of Toll-like receptor 9 (TLR9) and myeloid differentiation factor 88 (MyD88) expression was performed via their related inhibitors, while pre-treatment of exogenous mtDNA was used to verify the role of mtDNA in stretching-induced inflammatory response and injury.ResultsUsing a cell culture model of CS, we found that knocking down PINK1 in lung epithelial cells reduced mitophagy activation and mtDNA release, leading to milder inflammatory response and injury; conversely, up-regulating PINK1 exacerbated stretching-induced inflammation and injury, and similar effects were observed by upregulating TLR9 to induce expression of MyD88 and nuclear factor-κB (NF-κB)/p65. Down-regulating MyD88 protected lung epithelial cells from stretching injury and decreased NF-κB/p65 expression.ConclusionThese findings suggest that PINK1-dependent mitophagy and associated TLR9 activation is indeed a major factor in stretch-induced cell injury via a mechanism in which released mtDNA activates TLR9 and thereby the MyD88/NF-κB pathway. Inhibiting this process may be a therapeutic approach to prevent inflammation and cell injury in patients on mechanical ventilation.https://www.frontiersin.org/article/10.3389/fcell.2020.00819/fullmitophagymitochondrial DNAToll-like receptor 9mechanical stretchinglung injury |
| spellingShingle | Ren Jing Ren Jing Zhao-Kun Hu Zhao-Kun Hu Fei Lin Fei Lin Sheng He Sheng He Sui-Sui Zhang Sui-Sui Zhang Wan-Yun Ge Wan-Yun Ge Hui-jun Dai Hui-jun Dai Xue-Ke Du Xue-Ke Du Jin-Yuan Lin Jin-Yuan Lin Ling-Hui Pan Ling-Hui Pan Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB Pathway Frontiers in Cell and Developmental Biology mitophagy mitochondrial DNA Toll-like receptor 9 mechanical stretching lung injury |
| title | Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB Pathway |
| title_full | Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB Pathway |
| title_fullStr | Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB Pathway |
| title_full_unstemmed | Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB Pathway |
| title_short | Mitophagy-Mediated mtDNA Release Aggravates Stretching-Induced Inflammation and Lung Epithelial Cell Injury via the TLR9/MyD88/NF-κB Pathway |
| title_sort | mitophagy mediated mtdna release aggravates stretching induced inflammation and lung epithelial cell injury via the tlr9 myd88 nf κb pathway |
| topic | mitophagy mitochondrial DNA Toll-like receptor 9 mechanical stretching lung injury |
| url | https://www.frontiersin.org/article/10.3389/fcell.2020.00819/full |
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