The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation
Abstract The innate immune response is the main pathophysiological process of ocular surface diseases exposed to multiple environmental stresses. The epithelium is central to the innate immune response, but whether and how innate immunity is initiated by ocular epithelial cells in response to variou...
| প্রধান লেখক: | , , , , , , , |
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| বিন্যাস: | প্রবন্ধ |
| ভাষা: | English |
| প্রকাশিত: |
Nature Publishing Group
2023-09-01
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| মালা: | Signal Transduction and Targeted Therapy |
| অনলাইন ব্যবহার করুন: | https://doi.org/10.1038/s41392-023-01624-z |
| _version_ | 1827707999896993792 |
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| author | Weijie Ouyang Shoubi Wang Dan Yan Jieli Wu Yunuo Zhang Wei Li Jiaoyue Hu Zuguo Liu |
| author_facet | Weijie Ouyang Shoubi Wang Dan Yan Jieli Wu Yunuo Zhang Wei Li Jiaoyue Hu Zuguo Liu |
| author_sort | Weijie Ouyang |
| collection | DOAJ |
| description | Abstract The innate immune response is the main pathophysiological process of ocular surface diseases exposed to multiple environmental stresses. The epithelium is central to the innate immune response, but whether and how innate immunity is initiated by ocular epithelial cells in response to various environmental stresses in ocular surface diseases, such as dry eye, is still unclear. By utilizing two classic experimental dry eye models—a mouse ocular surface treated with benzalkonium chloride (BAC) and a mouse model with surgically removed extraorbital lachrymal glands, as well as dry eye patient samples—along with human corneal epithelial cells (HCE) exposed to hyperosmolarity, we have discovered a novel innate immune pathway in ocular surface epithelial cells. Under stress, mitochondrial DNA (mtDNA) was released into the cytoplasm through the mitochondrial permeability transition pore (mPTP) and further activated the cyclic GMP-AMP synthase (cGAS)—stimulator of interferon genes (STING) pathway, aggravating downstream inflammatory responses and ocular surface damage. Genetic deletion or pharmacological suppression of STING and inhibition of mtDNA release reduced inflammatory responses, whereas mtDNA transfection supported cytoplasmic mtDNA-induced inflammatory responses by activating the cGAS-STING pathway. Our study clarified the cGAS-STING pathway-dependent sensing of mitochondrial DNA-mediated ocular surface inflammation, which elucidated a new mechanism of ocular surface diseases in response to multiple environmental stresses. |
| first_indexed | 2024-03-10T16:57:31Z |
| format | Article |
| id | doaj.art-0d3d0386231f43ba8acfc6499dcb603f |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-03-10T16:57:31Z |
| publishDate | 2023-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-0d3d0386231f43ba8acfc6499dcb603f2023-11-20T11:04:55ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-09-018111210.1038/s41392-023-01624-zThe cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammationWeijie Ouyang0Shoubi Wang1Dan Yan2Jieli Wu3Yunuo Zhang4Wei Li5Jiaoyue Hu6Zuguo Liu7Xiamen University affiliated Xiamen Eye Center; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen UniversityXiamen University affiliated Xiamen Eye Center; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen UniversityXiamen University affiliated Xiamen Eye Center; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen UniversityChangsha Aier Eye HospitalXiamen University affiliated Xiamen Eye Center; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen UniversityXiamen University affiliated Xiamen Eye Center; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen UniversityXiamen University affiliated Xiamen Eye Center; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen UniversityXiamen University affiliated Xiamen Eye Center; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen UniversityAbstract The innate immune response is the main pathophysiological process of ocular surface diseases exposed to multiple environmental stresses. The epithelium is central to the innate immune response, but whether and how innate immunity is initiated by ocular epithelial cells in response to various environmental stresses in ocular surface diseases, such as dry eye, is still unclear. By utilizing two classic experimental dry eye models—a mouse ocular surface treated with benzalkonium chloride (BAC) and a mouse model with surgically removed extraorbital lachrymal glands, as well as dry eye patient samples—along with human corneal epithelial cells (HCE) exposed to hyperosmolarity, we have discovered a novel innate immune pathway in ocular surface epithelial cells. Under stress, mitochondrial DNA (mtDNA) was released into the cytoplasm through the mitochondrial permeability transition pore (mPTP) and further activated the cyclic GMP-AMP synthase (cGAS)—stimulator of interferon genes (STING) pathway, aggravating downstream inflammatory responses and ocular surface damage. Genetic deletion or pharmacological suppression of STING and inhibition of mtDNA release reduced inflammatory responses, whereas mtDNA transfection supported cytoplasmic mtDNA-induced inflammatory responses by activating the cGAS-STING pathway. Our study clarified the cGAS-STING pathway-dependent sensing of mitochondrial DNA-mediated ocular surface inflammation, which elucidated a new mechanism of ocular surface diseases in response to multiple environmental stresses.https://doi.org/10.1038/s41392-023-01624-z |
| spellingShingle | Weijie Ouyang Shoubi Wang Dan Yan Jieli Wu Yunuo Zhang Wei Li Jiaoyue Hu Zuguo Liu The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation Signal Transduction and Targeted Therapy |
| title | The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation |
| title_full | The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation |
| title_fullStr | The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation |
| title_full_unstemmed | The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation |
| title_short | The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation |
| title_sort | cgas sting pathway dependent sensing of mitochondrial dna mediates ocular surface inflammation |
| url | https://doi.org/10.1038/s41392-023-01624-z |
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