The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
The dendritic cell-T helper 17-macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia.
复制标题
DOI：
10.1002/hep.28851
复制
发表时间：
2017-01
期刊：
影响因子：
13.5
通讯作者：
Miethke, Alexander G.
中科院分区：
文献类型：
--
作者：
Lages, Celine S.;Simmons, Julia;Maddox, Avery;Jones, Keaton;Karns, Rebekah;Sheridan, Rachel;Shanmukhappa, Shiva Kumar;Mohanty, Sujit;Kofron, Matthew;Russo, Pierre;Wang, Yui-Hsi;Chougnet, Claire;Miethke, Alexander G.
胆道闭锁是新生儿肝外胆管树的纤维炎性阻塞。虽然诊断时肝内胆管增生是普遍存在的，但后来出现胆管缺乏。我们假设极化 T 辅助淋巴细胞反应协调了这种疾病中肝内胆道损伤的进展。 IL-17A-GFP、CD11c/DTR 和 IL17RA−/− 小鼠用于检查恒河猴轮状病毒诱导的胆道闭锁中的 T 淋巴细胞极化、炎性白细胞募集和胆道损伤。将多参数流式细胞术和免疫染色自动图像分析应用于胆道闭锁婴儿的肝组织样本。在小鼠模型中，病毒攻击后第 8 天，激活的 CD4+ 淋巴细胞开始在肝脏中出现，同时先天免疫反应减弱。血浆 IL-17A 水平随着 Th17 淋巴细胞和髓样树突细胞的肝脏积聚而升高。靶向清除 CD11c+ 树突状细胞可减少肝脏 IL-17A 的产生并改善肝内胆管损伤。重组IL17A在体外诱导新生儿胆管细胞中CCL2的表达，并且阻断相应的趋化因子受体CCR2可减少体内炎症巨噬细胞向肝脏的募集。 IL-17A 信号传导的基因破坏与肝脏 Ccl2/Ccr2 mRNA 表达下调、炎症性 Ly6Chi 巨噬细胞对肝脏的浸润减少以及生存率提高有关。在胆道闭锁婴儿的肝脏中，发现胆管细胞表达IL-17受体A，且IL-17A+细胞的患病率与诊断时CD68+巨噬细胞浸润程度呈正相关。在接受肝移植的疾病进展患者中，肝脏 CD4+ 淋巴细胞是 IL-17A 的主要产生者。我们的研究结果将树突状细胞-Th17-巨噬细胞轴确定为开发策略的目标，以阻止胆道闭锁患者肝内胆管损伤的进展。
Biliary atresia is a fibroinflammatory obstruction of the extrahepatic biliary tree in neonates. While intrahepatic bile duct proliferation is universal at diagnosis, bile duct paucity develops later. We hypothesized that polarized T helper lymphocyte responses orchestrate progression of intrahepatic biliary injury in this disease. IL-17A-GFP, CD11c/DTR and IL17RA−/− mice were used to examine T-lymphocyte polarization, inflammatory leukocyte recruitment and biliary injury in rhesus-rotavirus induced biliary atresia. Multiparameter flow cytometry and automated image analysis of immunostaining were applied to liver tissue samples from infants with biliary atresia. In the mouse model, activated CD4+ lymphocytes started to emerge in the liver on day 8 after viral challenge while innate immune responses were waning. Plasma IL-17A levels rose concomitant with hepatic accumulation of Th17 lymphocytes and myeloid dendritic cells. Targeted depletion of CD11c+ dendritic cells diminished hepatic IL-17A production and ameliorated intrahepatic bile duct injury. Recombinant IL17A induced expression of CCL2 in neonatal cholangiocytes in vitro, and blockade of the corresponding chemokine receptor CCR2 reduced recruitment of inflammatory macrophages to the liver in vivo. Genetic disruption of IL-17A signaling was associated with downregulation of hepatic Ccl2/Ccr2 mRNA expression, reduced infiltration of the liver with inflammatory Ly6Chi macrophages and improved survival. In the liver of infants with biliary atresia, cholangiocytes were found to express IL-17 receptor A and the prevalence of IL-17A+ cells was positively correlated with the degree of CD68+ macrophage infiltration at diagnosis. Hepatic CD4+ lymphocytes were chief producers of IL-17A in patients with progressive disease undergoing liver transplantation. Our findings identify the dendritic cell-Th17-macrophage axis as target for the development of strategies to block progression of intrahepatic bile duct injury in patients with biliary atresia.
登录
查看更多内容
影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
影响因子：
17.1
作者：
Saxena V;Shivakumar P;Sabla G;Mourya R;Chougnet C;Bezerra JA
通讯作者：
Bezerra JA
影响因子：
29.4
作者：
Meng F;Wang K;Aoyama T;Grivennikov SI;Paik Y;Scholten D;Cong M;Iwaisako K;Liu X;Zhang M;Österreicher CH;Stickel F;Ley K;Brenner DA;Kisseleva T
通讯作者：
Kisseleva T
DOI：
10.1097/mpg.0000000000000986
发表时间：
2016-02-01
影响因子：
2.9
作者：
Arnon, Ronen;Annunziato, Rachel A.;Shneider, Benjamin L.
通讯作者：
Shneider, Benjamin L.
影响因子：
25.7
作者：
Miethke AG;Saxena V;Shivakumar P;Sabla GE;Simmons J;Chougnet CA
通讯作者：
Chougnet CA