Ozone exposure affects corneal epithelial fate by promoting mtDNA leakage and cGAS/STING activation

• Published in: Journal of hazardous materials 2024-03, Vol.465, p.133219, Article 133219
• Main Authors: Fan, Kai, Dong, Nuo, Fang, Meichai, Xiang, Zixun, Zheng, Lan, Wang, Mengyuan, Shi, Yukuan, Tan, Gang, Li, Cheng, Xue, Yuhua
• Format: Article
• Language: English
• Subjects: CGAS/STING; MtDNA; Ozone; Squamous metaplasia
• ISSN: 0304-3894; 1873-3336; 1873-3336
• DOI: 10.1016/j.jhazmat.2023.133219

Ozone is a common air pollutant associated with various human diseases. The human ocular surface is frequently exposed to ozone in the troposphere, but the mechanisms by which ozone affects the ocular surface health remain unclear. This study aimed to establish a mouse model to investigate the effects of ozone exposure on the ocular surface and the corneal epithelium. The findings revealed that ozone exposure disrupted corneal epithelial homeostasis and differentiation, resulting in corneal squamous metaplasia. Further, ozone exposure induced oxidative damage and cytoplasmic leakage of mitochondrial DNA (mtDNA), thereby activating the cGAS/STING signaling pathway. The activation of the cGAS/STING signaling pathway triggered the activation of downstream NF-κB and TRAF6 signaling pathways, causing corneal inflammation, thereby promoting corneal inflammation and squamous metaplasia. Finally, C-176, a selective STING inhibitor, effectively prevented and treated corneal inflammation and squamous metaplasia caused by ozone exposure. This study revealed the role of mtDNA leakage-mediated cGAS/STING activation in corneal squamous epithelial metaplasia caused by ozone exposure. It also depicted the abnormal expression pattern of corneal epithelial keratin using three-dimensional images, providing new targets and strategies for preventing and treating corneal squamous metaplasia and other ocular surface diseases. [Display omitted] •Ozone disrupted corneal epithelial homeostasis.•Ozone exposure affected keratin expression patterns.•Ozone induced DNA damage and abnormal mitosis in corneal epithelial cells.•Ozone induced mtDNA leakage and cGAS/STING activation.•cGAS/STING pathway inhibition could treat corneal squamous metaplasia.