β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction.
β-Catenin-NF-κB-CFTR interactions in cholangiocytes regulate inflammation and fibrosis during ductular reaction.
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胆管细胞中的β-catenin-NF-κB-CFTR相互作用调节导管反应过程中的炎症和纤维化。
DOI：
10.7554/elife.71310
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发表时间：
2021-10-05
期刊：
影响因子：
7.7
通讯作者：
Monga SP
中科院分区：
文献类型：
--
作者：
Hu S;Russell JO;Liu S;Cao C;McGaughey J;Rai R;Kosar K;Tao J;Hurley E;Poddar M;Singh S;Bell A;Shin D;Raeman R;Singhi AD;Nejak-Bowen K;Ko S;Monga SP
胆管反应(DR)期间胆管上皮细胞(BECs)的扩张在囊性纤维化(CF)等肝脏疾病中可观察到，并与炎症和纤维化相关，尽管其潜在机制尚不完全清楚。使用两种不同的基因敲除的小鼠，一种是肝细胞和BECs(KO1)，另一种是只丢失肝细胞(KO2)的β-Catenin基因敲除小鼠，我们证明了在两周胆碱缺乏的乙硫氨酸补充饮食的初始损伤后，不同的长期修复。KO2显示BEC来源的β-catenin阳性肝细胞逐渐在肝脏再生，损伤消失。KO1显示β-连环蛋白持续缺失，BEC中NF-κB活化，进行性DR和纤维化，这与CF的组织学特征相似。我们发现了β-连环蛋白、核因子κB和跨膜电导调节因子在内皮细胞中的相互作用。Cftr或β-catenin的缺失导致了核因子-κB的激活、DR和炎症。因此，我们在BEC中发现了一个新的β-连环蛋白-核因子κB-cftr相互作用体，它的破坏可能参与了肝纤维化的病理过程。肝脏具有令人难以置信的自我修复或“再生”能力--也就是说，它有能力用新组织取代受损组织。为了做到这一点，器官依靠肝细胞(形成肝脏的细胞)和胆管细胞(形成胆管的细胞)分裂并相互转化，以修复和替换受损的组织，以防受到严重的侮辱。在长期或慢性肝损伤期间，胆管细胞会经历一种称为“胆管反应”的过程，这种反应会导致细胞增殖并产生刺激炎症的蛋白质，并可能导致肝脏瘢痕形成(纤维化)。胆管反应是严重肝病的标志，不同的疾病表现出不同的特点。例如，在囊性纤维化中，一种独特的导管反应发生在晚期，同时伴有炎症和纤维化。尽管胆管反应在肝脏疾病中发挥了作用，但它在分子水平上是如何工作的还不是很清楚。Hu等人。着手研究一种名为β-catenin的蛋白质是如何参与导管反应的，这种蛋白质可以导致多种类型的细胞增殖。他们使用了三种类型的小鼠进行实验：野生型小鼠，非转基因小鼠；以及两种类型的转基因小鼠。其中一只突变小鼠在胆管细胞中不产生β-连环蛋白，而另一只在胆管细胞和肝细胞中都缺乏β-连环蛋白。在短暂的肝脏损伤后-胡等人。通过给小鼠喂食特定的食物引起的--野生型小鼠能够再生和修复肝脏，而不会出现任何导管反应。在肝细胞中缺乏β-连环蛋白的突变小鼠表现出暂时的胆管反应，并最终通过将胆管细胞转变为肝细胞来修复它们的肝脏。另一方面，在肝细胞和胆管细胞中都缺乏β-连环蛋白的突变小鼠表现出持续的胆管反应、炎症和纤维化，看起来像与囊性纤维化相关的肝病患者的情况。进一步的研究表明，β-catenin与一种名为ctfr的蛋白质相互作用，而ctfr与囊性纤维化有关。当胆管细胞缺乏这两种蛋白质中的任何一种时，另一种名为核因子-B的蛋白质被激活，导致胆管反应，导致炎症和纤维化。Hu等人的发现。阐明了β-连环蛋白在胆管反应中的作用。此外，结果表明β-连环蛋白、CTFR和核因子-B之间存在以前未知的相互作用，这可能导致未来更好地治疗囊性纤维化。
Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of β-catenin, one with β-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived β-catenin-positive hepatocytes and resolution of injury. KO1 showed persistent loss of β-catenin, NF-κB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of β-catenin, NFκB, and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or β-catenin led to NF-κB activation, DR, and inflammation. Thus, we report a novel β-catenin-NFκB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF. The liver has an incredible capacity to repair itself or ‘regenerate’ – that is, it has the ability to replace damaged tissue with new tissue. In order to do this, the organ relies on hepatocytes (the cells that form the liver) and bile duct cells (the cells that form the biliary ducts) dividing and transforming into each other to repair and replace damaged tissue, in case the insult is dire. During long-lasting or chronic liver injury, bile duct cells undergo a process called ‘ductular reaction’, which causes the cells to multiply and produce proteins that stimulate inflammation, and can lead to liver scarring (fibrosis). Ductular reaction is a hallmark of severe liver disease, and different diseases exhibit ductular reactions with distinct features. For example, in cystic fibrosis, a unique type of ductular reaction occurs at late stages, accompanied by both inflammation and fibrosis. Despite the role that ductular reaction plays in liver disease, it is not well understood how it works at the molecular level. Hu et al. set out to investigate how a protein called β-catenin – which can cause many types of cells to proliferate – is involved in ductular reaction. They used three types of mice for their experiments: wild-type mice, which were not genetically modified; and two strains of genetically modified mice. One of these mutant mice did not produce β-catenin in biliary duct cells, while the other lacked β-catenin both in biliary duct cells and in hepatocytes. After a short liver injury – which Hu et al. caused by feeding the mice a specific diet – the wild-type mice were able to regenerate and repair the liver without exhibiting any ductular reaction. The mutant mice that lacked β-catenin in hepatocytes showed a temporary ductular reaction, and ultimately repaired their livers by turning bile duct cells into hepatocytes. On the other hand, the mutant mice lacking β-catenin in both hepatocytes and bile duct cells displayed sustained ductular reactions, inflammation and fibrosis, which looked like that seen in patients with liver disease associated to cystic fibrosis. Further probing showed that β-catenin interacts with a protein called CTFR, which is involved in cystic fibrosis. When bile duct cells lack either of these proteins, another protein called NF-B gets activated, which causes the ductular reaction, leading to inflammation and fibrosis. The findings of Hu et al. shed light on the role of β-catenin in ductular reaction. Further, the results show a previously unknown interaction between β-catenin, CTFR and NF-B, which could lead to better treatments for cystic fibrosis in the future.