Ozone exposure affects corneal epithelial fate by promoting mtDNA leakage and cGAS/STING activation
Ozone exposure affects corneal epithelial fate by promoting mtDNA leakage and cGAS/STING activation
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DOI：
10.1016/j.jhazmat.2023.133219
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发表时间：
2023-12-14
影响因子：
13.6
通讯作者：
Xue，Yuhua
中科院分区：
文献类型：
--
作者：
Fan，Kai;Dong，Nuo;Xue，Yuhua
臭氧是一种常见的空气污染物，与各种人类疾病有关。人类眼表经常暴露于对流层中的臭氧，但臭氧影响眼表健康的机制仍不清楚。本研究旨在建立小鼠模型，研究臭氧暴露对眼表和角膜上皮的影响。结果显示，臭氧暴露破坏了角膜上皮的稳态和分化，导致角膜鳞状上皮化生。此外，臭氧暴露诱导线粒体DNA（mtDNA）的氧化损伤和细胞质渗漏，从而激活cGAS/STING信号通路。cGAS/STING信号通路的激活触发了下游NF-κB和TRAF 6信号通路的激活，引起角膜炎症，从而促进角膜炎症和鳞状上皮化生。最后，选择性STING抑制剂C-176有效预防和治疗臭氧暴露引起的角膜炎症和鳞状上皮化生。这项研究揭示了mtDNA泄漏介导的cGAS/STING激活在臭氧暴露引起的角膜鳞状上皮化生中的作用。利用三维图像描绘角膜上皮角蛋白的异常表达模式，为防治角膜鳞状上皮化生等眼表疾病提供新的靶点和策略。
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.