Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions
Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions
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DOI：
10.3390/cells9010190
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发表时间：
2020-01-01
期刊：
影响因子：
6
通讯作者：
Zhou, Huiping
中科院分区：
文献类型：
--
作者：
Li, Xiaojiaoyang;Liu, Runping;Zhou, Huiping
肝巨噬细胞的活化是促进胆汁淤积性肝损伤的关键驱动力。外泌体是几乎所有类型的细胞释放的重要的细胞外小泡，参与细胞间的通讯。我们先前报道了胆管细胞来源的外泌体长非编码RNA（lncRNA）H19在破坏肝细胞胆汁酸稳态和促进肝星状细胞（HSC）活化中起着至关重要的作用。来源于胆管细胞的外泌体H19被枯否细胞迅速摄取。然而，外泌体lncRNA H19和胆汁淤积中巨噬细胞驱动的炎症之间的机制联系仍不清楚。在此，我们报道了在Mdr 2（-/-）和胆管结扎（BDL）胆汁淤积小鼠模型以及人原发性硬化性胆管炎（PSC）和原发性胆汁性胆管炎（PBC）患者中，肝脏H19水平与巨噬细胞活化和肝纤维化密切相关。外泌体H19可显著诱导枯否细胞表达和分泌趋化因子（C-C基序）配体2（CCL-2）和白细胞介素6（IL-6）。富含H19的外泌体增强枯否细胞的活化M1极化，并促进骨髓源性巨噬细胞的募集和分化，这被CCL-2药理学抑制剂抑制。总之，胆管细胞来源的外泌体H19通过CCL-2/CCR-2信号通路在巨噬细胞活化、分化和趋化性中发挥关键作用，这代表了胆汁淤积性肝病的治疗靶点。
Activation of hepatic macrophages represents the critical driving force to promote cholestatic liver injury. Exosomes, as important small extracellular vesicles released by almost all types of cells, contribute to intercellular communication. We previously reported that cholangiocyte-derived exosomal long noncoding RNA (lncRNA) H19 plays a vital role in disrupting bile acid homeostasis in hepatocytes and promoting the activation of hepatic stellate cells (HSCs). Exosomal H19 derived from cholangiocytes was rapidly taken up by Kupffer cells. However, the mechanistic links between exosomal lncRNA H19 and macrophage-driven inflammation in cholestasis remain unclear. Here, we reported that the hepatic H19 level was closely correlated with macrophage activation and hepatic fibrosis in both Mdr2(-/-) and bile duct ligation (BDL) cholestatic mouse models, as well as in human primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) patients. Exosomal H19 significantly induced the expression and secretion of chemokine (C-C motif) ligand 2 (CCL-2) and interleukin 6 (IL-6) in Kupffer cells. H19-enriched exosomes enhanced the activation M1 polarization of Kupffer cells and promoted the recruitment and differentiation of bone marrow-derived macrophages, which were inhibited by a CCL-2 pharmacological inhibitor. In conclusion, Cholangiocyte-derived exosomal H19 played a critical role in macrophage activation, differentiation, and chemotaxis through CCL-2/CCR-2 signaling pathways, which represent a therapeutic target for cholestatic liver diseases.