Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America.
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China.
PLoS One. 2020 Nov 2;15(11):e0239119. doi: 10.1371/journal.pone.0239119. eCollection 2020.
Autophagy is an important factor in liver ischemia-reperfusion injury. In the current study we investigate the function of interferon regulatory factor-1 (IRF1) in regulating autophagy to promote hepatic ischemia reperfusion injury (IR). The high expression of IRF1 during hepatic IR exhibited increased liver damage and was associated with activation of autophagy shown by Western blot markers, as well as immunofluorescent staining for autophagosomes. These effects were diminished by IRF1 deficiency in IRF1 knock out (KO) mice. Moreover, the autophagy inhibitor 3-MA decreased IR-induced liver necrosis and markedly abrogated the rise in liver injury tests (AST/ALT). β-catenin expression decreased during liver IR and was increased in the IRF1 KO mice. Immunoprecipitation assay showed the binding between IRF1 and β-catenin. Overexpression of IRF1 induced autophagy and also inhibited the expression of β-catenin. β-catenin inhibitor increased autophagy while β-catenin agonist suppressed autophagy in primary mouse hepatocytes. These results indicate that IRF1 induced autophagy aggravates hepatic IR injury in part by inhibiting β-catenin and suggests that targeting IRF1 may be an effective strategy in reducing hepatic IR injury.
自噬是肝脏缺血再灌注损伤的一个重要因素。在本研究中，我们研究了干扰素调节因子-1（IRF1）在调节自噬以促进肝缺血再灌注损伤（IR）中的功能。在肝 IR 期间，IRF1 的高表达表现出增加的肝损伤，并与自噬的激活相关，Western blot 标志物以及自噬体的免疫荧光染色显示。在 IRF1 敲除（KO）小鼠中，IRF1 缺乏可减弱这些作用。此外，自噬抑制剂 3-MA 减少了 IR 诱导的肝坏死，并显著降低了肝损伤试验（AST/ALT）的升高。在肝 IR 期间，β-catenin 的表达减少，在 IRF1 KO 小鼠中增加。免疫沉淀试验显示 IRF1 和 β-catenin 之间的结合。IRF1 的过表达诱导自噬，同时抑制β-catenin 的表达。β-catenin 抑制剂增加自噬，而β-catenin 激动剂抑制原代小鼠肝细胞中的自噬。这些结果表明，IRF1 诱导的自噬通过抑制β-catenin 加重肝脏 IR 损伤，提示靶向 IRF1 可能是减少肝脏 IR 损伤的有效策略。
