Sphingosine 1-Phosphate Receptor 2 and 3 Mediate Bone Marrow-Derived Monocyte/Macrophage Motility in Cholestatic Liver Injury in Mice.
Sphingosine 1-Phosphate Receptor 2 and 3 Mediate Bone Marrow-Derived Monocyte/Macrophage Motility in Cholestatic Liver Injury in Mice.
复制标题
1-磷酸鞘氨醇受体 2 和 3 介导小鼠胆汁淤积性肝损伤中骨髓源性单核细胞/巨噬细胞的运动
DOI：
10.1038/srep13423
复制
发表时间：
2015-09-01
影响因子：
4.6
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Yang L;Han Z;Tian L;Mai P;Zhang Y;Wang L;Li L
1-磷酸鞘氨醇（S1P）/S1P受体（S1PR）系统参与了肝损伤的病理过程。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源性单核细胞/巨噬细胞 (BMM) 迁移的影响，并确定该过程背后的信号通路。通过免疫荧光、RT-PCR 和 Western blot 来表征 BMM 中 S1PR1-3 的表达。在博伊登室中测定细胞迁移。 在体内，接受EGFP转基因小鼠的BM移植的嵌合体小鼠接受胆管结扎（BDL）手术，通过施用S1PR2/3拮抗剂诱导肝损伤。结果显示S1PR1-3均在BMMs中表达。 S1P通过S1PR2和S1PR3对BMMs发挥强大的迁移作用。此外，PTX 和 LY-294002（PI3K 抑制剂）可阻止 S1PR2/3 介导的 BMM 迁移，并且 JTE-013、CAY-10444 或 LY294002 抑制 S1P 引起的 Rac1 激活。体内给予 S1PR2/3 拮抗剂可显着减少 BDL 治疗小鼠的 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运动，这为S1P/S1PR在肝损伤中的作用提供了新的令人信服的信息，并为肝纤维化的药物治疗开辟了新的视角。
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. S1PR1–3expression 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 S1PR2/3antagonists. The results showed that S1PR1–3were all expressed in BMMs. S1P exerted a powerful migratory action on BMMs via S1PR2and 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 S1PR2/3antagonistsin vivosignificantly reduced BMM recruitment in BDL-treated mice and attenuated hepatic inflammation and fibrosis. In conclusion, S1P/S1PR2/3system 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.