The role of neonatal Gr-1+ myeloid cells in a murine model of rhesus-rotavirus induced biliary atresia
The role of neonatal Gr-1+ myeloid cells in a murine model of rhesus-rotavirus induced biliary atresia
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新生儿 Gr-1 骨髓细胞在恒河猴轮状病毒诱导胆道闭锁小鼠模型中的作用
DOI：
10.1016/j.ajpath.2018.07.024
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Zhang R;Lin Z;Fu M;Guan X;Yu J;Zhong W;Zeng J;Lui VCH;Tam PKH;Lamb JR;Xia H;Chen Y
胆道闭锁(BA)时先天免疫的激活与胆管细胞的损伤一起发生。然而，关于所涉及的炎症细胞的详细信息尚不清楚。本研究探讨了小鼠BA模型中CD11b+Gr-1+细胞的病理生理学及其在BA患者中的存在。用抗Ly6G抗体在接种恒河猴轮状病毒诱导的小鼠BA中靶向CD11b+Gr-1+细胞。在BA患者的活检组织中检测了Ly6G同源CD177+的表达。与单纯病毒治疗组相比，每3天每只小鼠注射5~10μg抗体4次，可明显改善BA的症状，延长小鼠的存活时间。然而，这些小鼠后来患上了慢性BA，并持续低体重和黄疸。与急性BA相比，肝组织炎性细胞减少。肝外胆管阻塞，而肝内胆管部分保留，肝纤维化进行性增加。这些小鼠体内存在高水平的CD11b+Gr-1+细胞。在这些慢性BA小鼠中再次注射抗Ly6G抗体可减少黄疸并恢复体重。在BBA患者中，CD177+细胞在肝脏中高表达。我们的研究结果表明，慢性小鼠BA模型与临床BA具有共同的关键特征，提示CD11b+Gr-1+细胞在BA的发生发展过程中具有重要作用。
Activation of innate immunity together with cholangiocyte damage occurs in biliary atresia (BA). However, detailed information on the inflammatory cells involved is lacking. This study investigates both the pathophysiology of CD11b+Gr-1+cells in a mouse model of BA and their presence in BA patients. CD11b+Gr-1+cells were targeted by an anti-Ly6G antibody in murine BA induced by inoculation with rhesus rotavirus. Expression of the Ly6G homolog CD177+was examined in biopsies from BA patients. The symptoms of BA were ameliorated, and survival was prolonged in those mice receiving 5 to 10 μg of antibody per mouse every 3 days for four times compared with the mice treated with virus alone. However, the mice later developed chronic BA with persistent low body weight and jaundice. Hepatic inflammatory cells were reduced compared with acute BA. Blockade of extrahepatic bile ducts occurred, whereas intrahepatic ductules were partially preserved, and a progressive increase in liver fibrosis was observed. High levels of CD11b+Gr-1+cells were present in these mice. The administration of an anti-Ly6G antibody again in those chronic BA mice reduced jaundice and restored body weight. In BA patients CD177+cells were highly expressed in the liver. Our data suggest that the chronic mouse BA model shares key characteristics with clinical BA and indicates the importance of CD11b+Gr-1+cells in the initiation and progression of BA.