Abstract：
Fatty liver, which is induced by abnormal lipid metabolism, is one of the most common causes of chronic liver disease globally and causes liver fibrosis. During this process, bone marrow-derived mesenchymal stromal cells (BMSCs) and hepatic stellate cells (HSCs) migrate toward the injured liver and participate in fibrogenesis by transdifferentiating into myofibroblasts. S100A8/A9 is a powerful inducer of cell migration and is involved in liver injury. But there are few reports about the effects of S100A8/A9 on BMSC/HSC migration. In the current study, we found that S100A8/A9 expression was increased during fatty liver injury/fibrogenesis. Moreover, S100A8/A9 expression had a positive correlation with fibrosis marker gene expressions in the injured liver. S100A8/A9 was mainly produced by neutrophils in the fibrotic liver. In vitro, neutrophil-secreted S100A8/A9 promoted BMSC/HSC migration via remodeling of microfilaments. Using specific siRNA and inhibitor, we proved that S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. Moreover, S100A8/A9 knock-down alleviated liver injury and fibrogenesis in vivo, while injection of S100A9 neutralizing antibody performed similar roles. We proved that S100A8/A9 was involved in liver injury and fibrogenesis via inducing BMSC/HSC migration. Our research reveals a new mechanism underlying BMSC/HSC migration in liver fibrosis and suggests S100A8/A9 as a potential therapeutic target of liver fibrosis. KEY MESSAGES: S100A8/A9 is secreted by neutrophils and increased in fatty liver injury. Neutrophil-secreted S100A8/A9 is a mediator of BMSC/HSC migration in vitro. S100A8/A9-induced BMSC/HSC migration is dependent on TLR4/Rho GTPases signaling. S100A8/A9 blockade alleviates liver injury and fibrogenesis in vivo.
摘要：
脂肪肝,这是由异常的脂质代谢引起的，是全球慢性肝病最常见的原因之一，并导致肝纤维化。在这个过程中,骨髓来源的间充质基质细胞（BMSCs）和肝星状细胞（HSCs）向受损的肝脏迁移，并通过转分化为肌成纤维细胞参与纤维形成。S100A8/A9是一种强大的细胞迁移诱导剂，参与肝损伤。但关于S100A8/A9对BMSC/HSC迁徙影响的报导较少。在目前的研究中,我们发现S100A8/A9表达在脂肪肝损伤/纤维化期间增加。此外，S100A8/A9表达与肝纤维化标志物基因表达呈正相关。S100A8/A9主要由纤维化肝脏中的中性粒细胞产生。体外，中性粒细胞分泌的S100A8/A9通过重塑微丝促进BMSC/HSC迁移。使用特异性siRNA和抑制剂，我们证明了S100A8/A9诱导的BMSC/HSC迁移依赖于TLR4/RhoGTPases信号传导。此外，S100A8/A9敲低减轻体内肝损伤和纤维化，而注射S100A9中和抗体起到类似的作用。我们证明S100A8/A9通过诱导BMSC/HSC迁移参与肝损伤和纤维化形成。我们的研究揭示了BMSC/HSC在肝纤维化中迁移的新机制，并表明S100A8/A9是肝纤维化的潜在治疗靶标。主要信息：S100A8/A9由中性粒细胞分泌，在脂肪肝损伤中增加。中性粒细胞分泌的S100A8/A9是体外BMSC/HSC迁移的介质。S100A8/A9诱导的BMSC/HSC迁移依赖于TLR4/RhoGTPases信号传导。S100A8/A9阻断减轻体内肝损伤和纤维化。
