2. Academic Validation
  3. The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation

The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation

  • Signal Transduct Target Ther. 2023 Sep 21;8(1):371. doi: 10.1038/s41392-023-01624-z.
Weijie Ouyang # 1 2,  Shoubi Wang # 1 3,  Dan Yan 1 2,  Jieli Wu 4,  Yunuo Zhang 1 2,  Wei Li 1 2,  Jiaoyue Hu 5 6,  Zuguo Liu 7 8 9
Affiliations

Affiliations

  • 1 Xiamen 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 University, Xiamen, Fujian, 361005, China.
  • 2 Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, 361005, China.
  • 3 The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, China.
  • 4 Changsha Aier Eye Hospital, Changsha, Hunan, 410016, China.
  • 5 Xiamen 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 University, Xiamen, Fujian, 361005, China. [email protected].
  • 6 Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, 361005, China. [email protected].
  • 7 Xiamen 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 University, Xiamen, Fujian, 361005, China. [email protected].
  • 8 Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Xiamen, Fujian, 361005, China. [email protected].
  • 9 Department of Ophthalmology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, China. [email protected].
  • # Contributed equally.
PMID: 37735446 DOI: 10.1038/s41392-023-01624-z
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.

Figures
Products