Yang Le, Han Zhen, Tian Lei, Mai Ping, Zhang Yuanyuan, Wang Lin, Li Liying
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Sci Rep. 2015 Sep 1;5:13423. doi: 10.1038/srep13423.
Sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) system has been implicated in the pathological process of liver injury. This study was designed to evaluate the effects of S1P/S1PR on bone marrow-derived monocyte/macrophage (BMM) migration in mouse models of cholestatic liver injury, and identify the signaling pathway underlying this process. S1PR1-3 expression in BMM was characterized by immunofluorescence, RT-PCR and Western blot. Cell migration was determined in Boyden chambers. In vivo, the chimera mice, which received BM transplants from EGFP-transgenic mice, received an operation of bile duct ligation (BDL) to induce liver injury with the administration of S1PR2/3 antagonists. The results showed that S1PR1-3 were all expressed in BMMs. S1P exerted a powerful migratory action on BMMs via S1PR2 and S1PR3. Furthermore, PTX and LY-294002 (PI3K inhibitor) prevented S1PR2/3-mediated BMM migration, and Rac1 activation by S1P was inhibited by JTE-013, CAY-10444 or LY294002. Administration of S1PR2/3 antagonists in vivo significantly reduced BMM recruitment in BDL-treated mice, and attenuated hepatic inflammation and fibrosis. In conclusion, S1P/S1PR2/3 system mediates BMM motility by PTX-PI3K-Rac1 signaling pathway, which provides new compelling information on the role of S1P/S1PR in liver injury and opens new perspectives for the pharmacological treatment of hepatic fibrosis.
鞘氨醇-1-磷酸（S1P）/S1P受体（S1PR）系统与肝损伤的病理过程有关。本研究旨在评估S1P/S1PR对胆汁淤积性肝损伤小鼠模型中骨髓来源的单核细胞/巨噬细胞（BMM）迁移的影响，并确定该过程的信号通路。通过免疫荧光、RT-PCR和蛋白质印迹法对BMM中S1PR1-3的表达进行了表征。在博伊登小室中测定细胞迁移。在体内，接受来自EGFP转基因小鼠骨髓移植的嵌合小鼠接受胆管结扎（BDL）手术以诱导肝损伤，并给予S1PR2/3拮抗剂。结果表明，S1PR1-3均在BMM中表达。S1P通过S1PR2和S1PR3对BMM发挥强大的迁移作用。此外，百日咳毒素（PTX）和LY-294002（PI3K抑制剂）可阻止S1PR2/3介导的BMM迁移，JTE-013、CAY-10444或LY294002可抑制S1P对Rac1的激活。在体内给予S1PR2/3拮抗剂可显著减少BDL处理小鼠中的BMM募集，并减轻肝脏炎症和纤维化。总之，S1P/S1PR2/3系统通过PTX-PI3K-Rac1信号通路介导BMM的运动，这为S1P/S1PR在肝损伤中的作用提供了新的有力信息，并为肝纤维化的药物治疗开辟了新的前景。
