DNA sensing and associated type 1 interferon signaling contributes to progression of radiation-induced liver injury
DNA sensing and associated type 1 interferon signaling contributes to progression of radiation-induced liver injury
复制标题
DNA 传感和相关 1 型干扰素信号传导有助于辐射引起的肝损伤的进展
DOI：
10.1038/s41423-020-0395-x
复制
发表时间：
2020-03-19
影响因子：
24.1
通讯作者：
Zeng, Zhaochong
中科院分区：
文献类型：
--
作者：
Du, Shisuo;Chen, Genwen;Zeng, Zhaochong
暴露于电离辐射（IR）后的肝损伤，无论是意外的还是治疗性的，都可能导致肝功能障碍。目前，放射治疗（RT）用于各种癌症，包括肝细胞癌（HCC）;然而，治疗剂量受到放射性肝病（RILD）的限制，死亡率高。此外，RILD的精确分子机制仍然知之甚少。在这里，我们研究了RILD的发病机制，使用各种基因敲除小鼠品系进行全肝照射。我们发现，肝细胞释放大量的双链DNA（dsDNA）照射后。非实质细胞（NPC）中的cGAS-STING途径被该dsDNA迅速激活，引起干扰素（IFN）-I产生和释放以及伴随的肝细胞损伤。IFN-1信号通路的遗传学和药理学消融可保护患者免受RILD的侵害。此外，临床辐照的人HCC周围肝组织表现出比未辐照组织显著更高的STING和IFNβ表达。放疗后血清IFNβ浓度升高与患者发生RILD相关。这些结果描述了cGAS-STING诱导的NPC中1型干扰素释放作为IR诱导的肝损伤的关键介质，并描述了先天免疫驱动的病理学机制，将cGAS-STING激活与初始辐射诱导的肝损伤的放大联系起来。
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.