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Galectin-3 modulates phagocytosis-induced stellate cell activation and liver fibrosis in vivo

机译:Galectin-3在体内调节吞噬作用诱导的星状细胞激活和肝纤维化

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Hepatic stellate cells (HSC), the key fibrogenic cells of the liver, transdifferentiate into myofibro-blasts upon phagocytosis of apoptotic hepatocytes. Galectin-3, a beta-galactoside-binding lectin, is a regulator of the phagocytic process. In this study, our aim was to study the mechanism by which extracellular galectin-3 modulates HSC phagocytosis and activation. The role of galectin-3 in engulfment was evaluated by phagocytosis and integrin binding assays in primary HSC. Galectin-3 expression was studied by real-time PCR and enzyme-linked immunosorbent assay, and in vivo studies were done in wild-type and galectin-3~(-/-) mice. We found that HSC from galectin-3~(-/-) mice displayed decreased phagocytic activity, expression of transforming growth factor-beta1, and procollagen alpha1(I). Recombinant galectin-3 reversed this defect, suggesting that extracellular galectin-3 is required for HSC activation. Galectin-3 facilitated the alpha_Vbeta_3 heterodimer-dependent binding, indicating that galectin-3 modulates HSC phagocytosis via cross-linking this integrin and enhancing the tethering of apoptotic cells. Blocking integrin alpha_Vbeta_3 resulted in decreased phagocytosis. Galectin-3 expression and release were induced in active HSC engulfing apoptotic cells, and this was mediated by the nuclear factor-kappaB signaling. The upregulation of galectin-3 in active HSC was further confirmed in vivo in bile duct-ligated (BDL) rats. Galectin-3~(-/-) mice displayed significantly decreased fibrosis, with reduced expression of alpha-smooth muscle actin and procollagen alpha1(I) following BDL. In summary, extracellular galectin-3 plays a key role in liver fibrosis by mediating HSC phagocytosis, activation, and subsequent autocrine and paracrine signaling by a feedforward mechanism.
机译:肝星状细胞(HSC)是肝脏的主要成纤维细胞,在凋亡性肝细胞被吞噬时会分化为成肌纤维细胞。 Galectin-3是一种β-半乳糖苷结合凝集素,是吞噬过程的调节剂。在这项研究中,我们的目的是研究细胞外半乳糖凝集素3调节HSC吞噬作用和激活的机制。 galectin-3在吞噬中的作用通过原发性HSC中的吞噬作用和整联蛋白结合测定进行了评估。通过实时荧光定量PCR和酶联免疫吸附试验研究了galectin-3的表达,并在野生型和galectin-3〜(-/-)小鼠中进行了体内研究。我们发现,来自galectin-3〜(-/-)小鼠的HSC显示出吞噬活性降低,转化生长因子β1和前胶原α1(I)的表达降低。重组galectin-3逆转了这一缺陷,表明HSC激活需要细胞外galectin-3。 Galectin-3促进了alpha_Vbeta_3异二聚体依赖性结合,表明Galectin-3通过交联该整联蛋白并增强凋亡细胞的束缚来调节HSC吞噬作用。阻断整联蛋白α_Vbeta_3导致吞噬作用降低。 Galectin-3的表达和释放在吞噬活跃的HSC的凋亡细胞中被诱导,这是由核因子-κB信号传导介导的。胆管结扎(BDL)大鼠体内进一步证实了活跃HSC中galectin-3的上调。 Galectin-3〜(-/-)小鼠显示出明显的纤维化减少,BDL后α平滑肌肌动蛋白和前胶原α1(I)的表达降低。总之,细胞外半乳糖凝集素3通过前馈机制介导HSC吞噬作用,激活以及随后的自分泌和旁分泌信号传导,在肝纤维化中起关键作用。

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