DNA sensing and associated type 1 interferon signaling contributes to progression of radiation-induced liver injury |
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Authors: | Shisuo Du Genwen Chen Baoying Yuan Yong Hu Ping Yang Yixing Chen Qianqian Zhao Jian Zhou Jia Fan Zhaochong Zeng |
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Affiliation: | 1.Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China ;2.Liver Surgery Department, Zhongshan Hospital, Fudan University, Shanghai, 200032 China |
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Abstract: | Liver damage upon exposure to ionizing radiation (IR), whether accidental or therapeutic, can contribute to liver dysfunction. Currently, radiotherapy (RT) is used for various cancers including hepatocellular carcinoma (HCC); however, the treatment dose is limited by radiation-induced liver disease (RILD) with a high mortality rate. Furthermore, the precise molecular mechanisms of RILD remain poorly understood. Here, we investigated RILD pathogenesis using various knockout mouse strains subjected to whole-liver irradiation. We found that hepatocytes released a large quantity of double-stranded DNA (dsDNA) after irradiation. The cGAS-STING pathway in non-parenchymal cells (NPCs) was promptly activated by this dsDNA, causing interferon (IFN)-I production and release and concomitant hepatocyte damage. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against RILD. Moreover, clinically irradiated human peri-HCC liver tissues exhibited substantially higher STING and IFNβ expression than non-irradiated tissues. Increased serum IFNβ concentrations post-radiation were associated with RILD development in patients. These results delineate cGAS-STING induced type 1 interferon release in NPCs as a key mediator of IR-induced liver damage and described a mechanism of innate-immunity-driven pathology, linking cGAS-STING activation with amplification of initial radiation-induced liver injury. |
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Keywords: | radiation-induced liver disease dsDNA cGAS-STING type 1 interferon |
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