ADAR1 Prevents Liver Injury from Inflammation and Suppresses Interferon Production in Hepatocytes
ADAR1 Prevents Liver Injury from Inflammation and Suppresses Interferon Production in Hepatocytes
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ADAR1 可防止炎症引起的肝损伤并抑制肝细胞中干扰素的产生
DOI：
10.1016/j.ajpath.2015.08.002
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发表时间：
2015-12-01
影响因子：
6
通讯作者：
Wang，Qingde
中科院分区：
文献类型：
--
作者：
Wang，Guoliang;Wang，Hui;Wang，Qingde
腺苷脱氨酶作用于RNA 1（ADAR 1）是胚胎肝脏发育的必需蛋白。ADAR 1缺失是胚胎致死的，因为严重的肝损伤。尽管肝脏特异性条件性基因敲除（Alb-ADAR 1 KO）小鼠证明，成人肝脏需要ADAR 1来防止肝细胞死亡，但其机制仍然难以捉摸。我们系统地分析了Alb-ADAR 1 KO小鼠的肝损伤。在来自Alb-ADAR 1 KO和同窝对照的肝组织中检查分化基因和炎症通路。诱导型ADAR 1 KO小鼠用于验证ADAR 1对炎性细胞因子的调节作用。我们发现，由于肝脏严重的结构和功能损伤，Alb-ADAR 1 KO小鼠表现出显著的生长迟缓和高死亡率，表现出压倒性的炎症、细胞死亡、纤维化、脂肪改变和代偿性再生。同时，Alb-ADAR 1 KO显示关键分化基因的表达改变和肝脏炎症细胞因子（尤其是I型干扰素）水平显著升高，这也通过原代肝细胞培养物中的可诱导ADAR 1敲低得到证实。我们的结论是ADAR 1是维持成人肝脏稳态的重要分子，反过来，形态和功能的完整性。它抑制I型干扰素和其他炎性细胞因子的产生。我们的研究结果可能为过度炎症反应引起的肝脏疾病（包括自身免疫性肝炎）的发病机制提供新的见解。
Adenosine deaminase acting on RNA 1 (ADAR1) is an essential protein for embryonic liver development. ADAR1 loss is embryonically lethal because of severe liver damage. Although ADAR1 is required in adult livers to prevent liver cell death, as demonstrated by liver-specific conditional knockout (Alb-ADAR1KO) mice, the mechanism remains elusive. We systematically analyzed Alb-ADAR1KOmice for liver damage. Differentiation genes and inflammatory pathways were examined in hepatic tissues from Alb-ADAR1KOand littermate controls. Inducible ADAR1 KO mice were used to validate regulatory effects of ADAR1 on inflammatory cytokines. We found that Alb-ADAR1KOmice showed dramatic growth retardation and high mortality because of severe structural and functional damage to the liver, which showed overwhelming inflammation, cell death, fibrosis, fatty change, and compensatory regeneration. Simultaneously, Alb-ADAR1KOshowed altered expression of key differentiation genes and significantly higher levels of hepatic inflammatory cytokines, especially type I interferons, which was also verified by inducible ADAR1 knockdown in primary hepatocyte cultures. We conclude that ADAR1 is an essential molecule for maintaining adult liver homeostasis and, in turn, morphological and functional integrity. It inhibits the production of type I interferons and other inflammatory cytokines. Our findings may provide novel insight in the pathogenesis of liver diseases caused by excessive inflammatory responses, including autoimmune hepatitis.