Sphingosine 1-Phosphate Receptor 2 and 3 Mediate Bone Marrow-Derived Monocyte/Macrophage Motility in Cholestatic Liver Injury in Mice.
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.
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Le
L
Yang
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Zhen
Z
Han
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Lei
L
Tian
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Ping
P
Mai
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Yuanyuan
Y
Zhang
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Lin
L
Wang
Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Liying
L
Li
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000032:analysis / Q000235:genetics; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000032:analysis / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D009479:Neuropeptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D018925:Chemokines; D002867:Chromones; D016207:Cytokines; D008246:Lysophospholipids; D009025:Morpholines; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D020830:rac1 GTP-Binding Protein; C471998:JTE 013; C484602:Rac1 protein, mouse; C578617:S1PR3 protein, rat; C556330:S1pr1 protein, mouse; C533955:sphingosine-1-phosphate receptor-2, mouse; C060506:sphingosine 1-phosphate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one