Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Liver Surgery Department, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Cell Mol Immunol. 2021 Jul;18(7):1718-1728. doi: 10.1038/s41423-020-0395-x. Epub 2020 Mar 19.
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.
暴露于电离辐射（IR）下会导致肝损伤，无论是意外的还是治疗性的，都会导致肝功能障碍。目前，放射疗法（RT）用于治疗各种癌症，包括肝细胞癌（HCC）；然而，由于放射性肝病（RILD）的治疗剂量有限，死亡率很高。此外，RILD 的精确分子机制仍知之甚少。在这里，我们使用各种经全肝照射的基因敲除小鼠品系研究了 RILD 的发病机制。我们发现照射后肝细胞会释放大量双链 DNA（dsDNA）。dsDNA 可迅速激活非实质细胞（NPC）中的 cGAS-STING 通路，导致干扰素（IFN）-I 的产生和释放，并伴随肝细胞损伤。IFN-I 信号通路的遗传和药理学消融可预防 RILD。此外，临床照射的 HCC 周围肝组织中 STING 和 IFNβ 的表达明显高于未照射组织。照射后血清 IFNβ 浓度的升高与患者 RILD 的发生有关。这些结果表明，cGAS-STING 诱导的 NPC 中 I 型干扰素释放是 IR 诱导肝损伤的关键介质，并描述了一种固有免疫驱动病理学的机制，将 cGAS-STING 激活与初始辐射诱导的肝损伤的放大联系起来。
