Li Dongling, Hu Minling, Liu Ying, Ye Peiying, Du Peishuang, Li Chi-Shan, Cheng Liang, Liu Ping, Jiang Jing, Su Lishan, Wang Shengdian, Zheng Pan, Liu Yang
1Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
OncoImmune-Suzhou, Suzhou, China.
Cell Discov. 2018 Feb 6;4:6. doi: 10.1038/s41421-017-0007-9. eCollection 2018.
It is generally assumed that inflammation following diethylnitrosamine (DEN) treatment promotes development of hepatocellular carcinoma (HCC) through the activity of intrahepatic macrophages. However, the tumor-promoting function of macrophages in the model has not been confirmed by either macrophage depletion or selective gene depletion in macrophages. Here we show that targeted mutation of dramatically increased HCC burden while reducing intrahepatic macrophages and DEN-induced hepatocyte apoptosis. Depletion of macrophages also increased HCC burden and reduced hepatocyte apoptosis, thus establishing macrophages as an innate effector recognizing DEN-induced damaged hepatocytes. Mechanistically, Cd24 deficiency increased the levels of p53 in macrophages, resulting in their depletion in mice following DEN treatment. These data demonstrate that the Cd24-p53 axis maintains intrahepatic macrophages, which can remove hepatocytes with DNA damage. Our data establish a critical role for macrophages in suppressing HCC development and call for an appraisal of the current dogma that intrahepatic macrophages promote HCC development.
一般认为，二乙基亚硝胺（DEN）处理后的炎症通过肝内巨噬细胞的活性促进肝细胞癌（HCC）的发展。然而，该模型中巨噬细胞的促肿瘤功能尚未通过巨噬细胞清除或巨噬细胞中的选择性基因缺失得到证实。在这里，我们表明，[基因名称]的靶向突变显著增加了HCC负担，同时减少了肝内巨噬细胞和DEN诱导的肝细胞凋亡。巨噬细胞的清除也增加了HCC负担并减少了肝细胞凋亡，从而将巨噬细胞确立为识别DEN诱导的受损肝细胞的先天性效应细胞。从机制上讲，Cd24缺乏会增加巨噬细胞中p53的水平，导致DEN处理后的[小鼠品系]小鼠体内巨噬细胞减少。这些数据表明，Cd24-p53轴维持肝内巨噬细胞，后者可以清除有DNA损伤的肝细胞。我们的数据确立了巨噬细胞在抑制HCC发展中的关键作用，并呼吁对目前认为肝内巨噬细胞促进HCC发展的教条进行重新评估。
