SAA1/TLR2 axis directs chemotactic migration of hepatic stellate cells responding to injury

Hepatic stellate cells (HSCs) are crucial for liver injury repair and cirrhosis. However, the mechanism of chemotactic recruitment of HSCs into injury loci is still largely unknown. Here, we demonstrate that serum amyloid A1 (SAA1) acts as a chemokine recruiting HSCs toward injury loci signaling via TLR2, a finding proven by gene manipulation studies in cell and mice models. The mechanistic investigations revealed that SAA1/TLR2 axis stimulates the Rac GTPases through PI3K-dependent pathways and induces phosphorylation of MLC (pSer19). Genetic deletion of TLR2 and pharmacological inhibition of PI3K diminished the phosphorylation of MLCpSer19 and migration of HSCs. In brief, SAA1 serves as a hepatic endogenous chemokine for the TLR2 receptor on HSCs, thereby initiating PI3K-dependent signaling and its effector, Rac GTPases, which consequently regulates actin filament remodeling and cell directional migration. Our findings provide novel targets for anti-fibrosis drug development.

肝星状细胞（HSCs）对于肝脏损伤修复和肝硬化至关重要。然而，HSCs向损伤部位的趋化性募集机制仍 largely 未知。本研究中，我们揭示了血清淀粉样蛋白A1（SAA1）作为一种趋化因子，通过Toll样受体2（TLR2）信号途径招募HSCs向损伤部位，这一发现通过细胞和鼠模型中的基因操作研究得到了证实。机制研究表明，SAA1/TLR2 轴通过PI3K依赖性途径激活Rac GTPases，并诱导MLC（pSer19）的磷酸化。TLR2的基因敲除和PI3K的药理学抑制减弱了MLCpSer19的磷酸化和HSCs的迁移。简言之，SAA1作为HSCs上TLR2受体的肝源内生性趋化因子，从而启动PI3K依赖性信号传导及其效应器Rac GTPases，进而调节肌动蛋白丝重排和细胞定向迁移。我们的研究为抗纤维化药物的开发提供了新的靶点。