Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, People's Republic of China.
Department of Infectious Disease, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, People's Republic of China.
Pediatr Res. 2017 Dec;82(6):1007-1016. doi: 10.1038/pr.2017.87. Epub 2017 Sep 6.
BackgroundBiliary atresia (BA) is an etiologically perplexing disease, manifested by neonatal cholestasis, repeated cholangitis, and progressive biliary fibrosis. MiR-155 has been implicated to modulate the immune response, which contributes to biliary injury. However, its potential role in the pathogenesis of BA has not been addressed so far.MethodsThe microRNA changes from BA patients and controls were identified via microarray. The immunomodulatory function of miR-155 was investigated via cell transfection and reporter assay. The lentiviral vector pL-miR-155 inhibitor was transfected into a mouse model to investigate its role in BA.ResultsThe expression of miR-155 in livers of BA patients was significantly increased, and an inverse correlation between miR-155 and suppressor of cytokine signaling 1 (SOCS1) was detected. MiR-155 overexpression promoted expressions of major histocompatibility complex (MHC) I, MHC II, Chemokine (C-X-C motif) ligand (CXCL) 9, CXCL10, monocyte chemotactic protein 1, and CXCL1 after IFN-γ stimulation, which could be suppressed by SOCS1 overexpression. Moreover, miR-155 overexpression activated JAK2/STAT3, thus enhancing the pro-inflammatory effect. Downregulating miR-155 reduced the incidence of BA in a rhesus monkey rotavirus-induced BA model.ConclusionOur results reveal a vital contribution of miR-155 upregulation and consequent SOCS1 downregulation to an immune response triggered via IFN-γ in BA.
背景
先天性胆道闭锁（BA）是一种病因复杂的疾病，表现为新生儿胆汁淤积、反复胆管炎和进行性胆管纤维化。miR-155 已被证明可调节免疫反应，从而导致胆管损伤。然而，其在 BA 发病机制中的潜在作用尚未得到解决。
方法
通过微阵列鉴定 BA 患者和对照者的 microRNA 变化。通过细胞转染和报告基因测定研究 miR-155 的免疫调节功能。将慢病毒载体 pL-miR-155 抑制剂转染到小鼠模型中，以研究其在 BA 中的作用。
结果
BA 患者肝脏中 miR-155 的表达明显增加，并且检测到 miR-155 与细胞因子信号转导抑制因子 1（SOCS1）呈负相关。miR-155 过表达可促进 MHC I、MHC II、趋化因子（C-X-C 基序）配体（CXCL）9、CXCL10、单核细胞趋化蛋白 1 和 CXCL1 在 IFN-γ 刺激后的表达，SOCS1 过表达可抑制其表达。此外，miR-155 过表达激活 JAK2/STAT3，从而增强促炎作用。下调 miR-155 可降低恒河猴轮状病毒诱导的 BA 模型中 BA 的发生率。
结论
我们的结果揭示了 miR-155 上调和随之而来的 SOCS1 下调对 BA 中 IFN-γ 触发的免疫反应的重要贡献。
