Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis.
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DOI：
10.1002/hep.28382
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Strazzabosco M
中科院分区：
文献类型：
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作者：
Locatelli L;Cadamuro M;Spirlì C;Fiorotto R;Lecchi S;Morell CM;Popov Y;Scirpo R;De Matteis M;Amenduni M;Pietrobattista A;Torre G;Schuppan D;Fabris L;Strazzabosco M
先天性肝纤维化（CHF）是一种胆道上皮疾病，其特征是胆管改变，类似于导管板畸形和进行性胆周纤维化，但没有明显的坏死性炎症。进行性肝纤维化会导致门静脉高压和肝功能衰竭，但导致 CHF 纤维化的机制仍不清楚。 CHF 是由 PKHD1 突变引起的，PKHD1 是编码纤维囊肿蛋白（一种在胆管细胞中表达的纤毛蛋白）的基因。使用与CHF同源的纤囊蛋白缺陷型(Pkhd1del4/del4)小鼠，我们发现Pkhd1del4/del4胆管细胞的特征是β-连环蛋白依赖性分泌一系列趋化因子，包括CXCL1、CXCL10和CXCL12，这些趋化因子刺激骨髓源性巨噬细胞的募集。我们还表明，Pkhd1del4/del4 胆管细胞反过来通过上调 αvβ6 整合素（潜在的局部 TGFβ1 激活剂）对巨噬细胞释放的促炎细胞因子做出反应。虽然巨噬细胞浸润最初以 M1 表型为主，但促纤维化的 M2 表型随着疾病进展而增加，门静脉肌成纤维细胞的数量也随之增加。与这些发现一致，氯膦酸盐诱导的巨噬细胞耗竭导致门静脉纤维化和门静脉高压以及肝囊肿的显着减少。我们的研究结果表明，上皮细胞功能障碍可能引发纤维化，导致低度炎症、巨噬细胞募集和胶原沉积。这些发现为胆道纤维化建立了一个新的范例，并代表了一个理解细胞功能障碍、副炎症、肝纤维化和巨噬细胞极化随时间变化之间关系的模型。
Congenital Hepatic Fibrosis (CHF) is a disease of the biliary epithelium characterized by bile duct changes resembling ductal plate malformations and by progressive peribiliary fibrosis, in the absence of overt necroinflammation. Progressive liver fibrosis leads to portal hypertension and liver failure, however the mechanisms leading to fibrosis in CHF remain elusive. CHF is caused by mutations in PKHD1, a gene encoding for fibrocystin, a ciliary protein expressed in cholangiocytes. Using a fibrocystin-defective (Pkhd1del4/del4) mouse, which is orthologous of CHF, we show that Pkhd1del4/del4 cholangiocytes are characterized by a β-catenin-dependent secretion of a range of chemokines, including CXCL1, CXCL10 and CXCL12, which stimulate bone marrow-derived macrophage recruitment. We also show that Pkhd1del4/del4 cholangiocytes, in turn, respond to proinflammatory cytokines released by macrophages by up-regulating αvβ6 integrin, an activator of latent local TGFβ1. While the macrophage infiltrate is initially dominated by the M1 phenotype, the profibrogenic M2 phenotype increases with disease progression, along with the number of portal myofibroblasts. Consistent with these findings, clodronate-induced macrophage depletion results in a significant reduction of portal fibrosis and portal hypertension as well as of liver cysts. our results show that fibrosis can be initiated by an epithelial cell dysfunction, leading to low-grade inflammation, macrophage recruitment and collagen deposition. These findings establish a new paradigm for biliary fibrosis and represent a model to understand the relationship between cell dysfunction, parainflammation, liver fibrosis and macrophage polarization over time.