The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity.
The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity.
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DOI：
10.1002/hep.28817
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发表时间：
2016-12
期刊：
影响因子：
13.5
通讯作者：
Strazzabosco, Mario
中科院分区：
文献类型：
--
作者：
Fiorotto, Romina;Villani, Ambra;Kourtidis, Antonis;Scirpo, Roberto;Amenduni, Mariangela;Geibel, Peter J.;Cadamuro, Massimiliano;Spirli, Carlo;Anastasiadis, Panos Z.;Strazzabosco, Mario
在肝脏中，CFTR 调节胆管上皮细胞（即胆管细胞）顶膜的胆汁分泌和其他功能。 CF相关肝病（CFLD）是CF患者死亡的主要原因。 CFTR 功能障碍会影响先天免疫途径，在肝脏和其他上皮细胞中产生副炎症状态。本研究调查了 CFTR 与 TLR4 活性的联系机制。我们发现 CFTR 与正常小鼠胆管细胞顶膜的多蛋白复合物相关，该复合物与负控制 Src 活性的蛋白相关。在 CFTR 缺陷的胆管细胞中，Src 酪氨酸激酶自我激活并磷酸化 TLR4，导致 NF-κB 激活，并增加响应内毒素的促炎细胞因子的产生。这种 Src/NF-κB 依赖性炎症过程会吸引炎症细胞，但也会引起顶端连接复合体的变化和上皮屏障功能的丧失。抑制 Src 可降低 CF 胆管细胞对 LPS 的炎症反应，挽救体外连接缺陷，并显着减轻内毒素诱导的体内胆道损伤和炎症（Cftr-KO 小鼠）。我们的研究结果揭示了 CFTR 作为胆管上皮细胞中 TLR4 反应和细胞极性调节剂的新功能。这种机制是致病性的，正如体内 Src 抑制的保护作用所表明的那样，并且可能是 CFLD 和其他炎症性胆管病的新治疗靶点。
In the liver, CFTR regulates bile secretion and other functions at the apical membrane of biliary epithelial cells (i.e cholangiocytes). CF-related liver disease (CFLD) is a major cause of death in patients with CF. CFTR dysfunction affects innate immune pathways, generating a para-inflammatory status in the liver, and other epithelia. This study investigates the mechanisms linking CFTR to TLR4 activity. We found that CFTR is associated in a multi-protein complex at the apical membrane of normal mouse cholangiocytes, with proteins that negatively control Src activity. In CFTR-defective cholangiocytes, Src tyrosine kinase self-activates and phosphorylates TLR4, resulting in activation of NF-κB, and increased pro-inflammatory cytokines production in response to endotoxins. This Src/NF-κB-dependent inflammatory process attracts inflammatory cells, but also generates changes in the apical junctional complex and loss of epithelial barrier function. Inhibition of Src decreased the inflammatory response of CF-cholangiocytes to LPS, rescued the junctional defect in-vitro and significantly attenuated endotoxin-induced biliary damage and inflammation in vivo (Cftr-KO mice). Our findings reveal a novel function of CFTR as regulator of TLR4 responses and cell polarity in biliary epithelial cells. This mechanism is pathogenetic, as shown by the protective effects of Src inhibition in vivo and maybe a novel therapeutic target in CFLD and other inflammatory cholangiopathies.
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DOI：
10.1083/jcb.201009141
发表时间：
2011-03-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Baum B;Georgiou M
通讯作者：
Georgiou M
影响因子：
6
作者：
Fouassier, Laura;Rosenberg, Peter;Housset, Chantal
通讯作者：
Housset, Chantal
影响因子：
29.4
作者：
Fiorotto, Romina;Spirli, Carlo;Strazzabosco, Mario
通讯作者：
Strazzabosco, Mario
DOI：
10.1002/hep.27565
发表时间：
2015-05
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Hatano R;Akiyama K;Tamura A;Hosogi S;Marunaka Y;Caplan MJ;Ueno Y;Tsukita S;Asano S
通讯作者：
Asano S
影响因子：
82.9
作者：
通讯作者：
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