Activation of Slit2-Robo1 signaling promotes liver fibrosis
Activation of Slit2-Robo1 signaling promotes liver fibrosis
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Slit2-Robo1 信号的激活可促进肝纤维化。
DOI：
10.1016/j.jhep.2015.07.033
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发表时间：
2015-12-01
影响因子：
25.7
通讯作者：
Wang, Lijing
中科院分区：
文献类型：
--
作者：
Chang, Jianlan;Lan, Tian;Wang, Lijing
背景与目的：分泌蛋白Slit2及其受体Robo1被认为调节细胞的生长和迁移。本研究旨在探讨Slit2-Robo1信号转导通路在肝纤维化发病机制中的作用。用四氯化碳(CCl4)诱导野生型(WT)、Slit2转基因(Slit2-TG)和Robo1(+/-)Robo2(+/-)双杂合子(Robo1/2(+/-))小鼠肝纤维化。采用原代小鼠肝星状细胞和人肝星状细胞株LX-2研究Slit2-Robo1信号在肝纤维化和肝星状细胞激活中的作用。结果：肝纤维化患者血清Slit2水平和肝组织中Slit2和Robo1的表达均显著升高。与WT小鼠相比，Slit2-TG小鼠更容易受到CCl4诱导的肝损伤，并更容易发展为肝纤维化。Slit2-TG小鼠肝纤维化的发生与肝脏I型胶原和α-平滑肌肌动蛋白(α-SMA)的表达增强有关。然而，CCl4处理的Robo1/2(+/-)小鼠的肝脏损伤以及肝脏I型胶原和α-SMA的表达都有所减轻。在体外，Robo1中和抗体R5和Robo1 siRNA下调HSC Smad2、Smad3、PI3K和AKT的磷酸化，而不依赖于转化生长因子-β1。R5和Robo1 siRNA也抑制HSC表达a-SMA。结论：Slit2-Robo1信号通路通过激活HSCs促进肝损伤和纤维化的发生。(C)2015年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: The secretory protein Slit2 and its receptor Robo1 are believed to regulate cell growth and migration. Here, we aimed to determine whether Slit2-Robo1 signaling mediates the pathogenesis of liver fibrosis.Methods: Serum levels of Slit2 in patients with liver fibrosis were determined by ELISA. Liver fibrosis was induced in wild-type (WT), Slit2 transgenic (Slit2-Tg) and Robo1(+/-)Robo2(+/-) double heterozygotes (Robo1/2(+/-)) mice by carbon tetrachloride (CCl4). The functional contributions of Slit2-Robo1 signaling in liver fibrosis and activation of hepatic stellate cells (HSCs) were investigated using primary mouse HSCs and human HSC cell line LX-2.Results: Significantly increased serum Slit2 levels and hepatic expression of Slit2 and Robo1 were observed in patients with liver fibrosis. Compared to WT mice, Slit2-Tg mice were much more vulnerable to CCl4-induced liver injury and more readily develop liver fibrosis. Development of hepatic fibrosis in Slit2-Tg mice was associated with a stronger hepatic expression of collagen I and a-smooth muscle actin (alpha-SMA). However, liver injury and hepatic expression of collagen I and alpha-SMA were attenuated in CCl4-treated Robo1/2(+/-) mice in response to CCl4 exposure. In vitro, Robo1 neutralizing antibody R5 and Robo1 siRNA downregulated phosphorylation of Smad2, Smad3, PI3K, and AKT in HSCs independent of TGF-beta 1. R5 and Robo1 siRNA also inhibited the expression of a-SMA by HSCs. Finally, the protective effect of R5 on the CCl4-induced liver injury and fibrosis was further verified in mice.Conclusions: Slit2-Robo1 signaling promotes liver injury and fibrosis through activation of HSCs. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.