title: Targeting S1P1 receptor protects against murine immunological hepatic injury through myeloid-derived suppressor cells.
abstract: Although FTY720 may alter migration and homing of lymphocytes via sphingosine-1-phosphate (S1P) receptors, our recent studies indicated that FTY720 directly controls the differentiation of Th1 cells to regulatory T cells (Tregs) by targeting S1P1. However, the pharmacological function of FTY720 in immunological hepatic injury remains unknown. In this study, the role and regulatory signaling pathway of S1P receptor were investigated using a pharmacological approach in immune-mediated hepatic injury (IMH). In the context of IMH, FTY720 significantly ameliorated mortality and hepatic pathology. In FTY720-treated mice, recruited CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) mediate protection against IMH and are functional suppressive immune modulators that result in fewer IFN-γ-producing Th1 cells and more Foxp3(+) Tregs. In agreement, FTY720-treated MDSCs promote the reciprocal differentiation between Th1 cells and Tregs in vitro and in vivo. Mechanistically, FTY720 treatment induced inducible NO synthase expression and NO production in MDSCs. Pharmacologic inhibition of inducible NO synthase completely eliminates MDSC suppressive function and eradicates their inducible effects on T cell differentiation. Finally, the mTOR inhibitor, rapamycin, photocopies the effects of FTY720 on MDSCs, implicating mTOR as a downstream effector of S1P1 signaling. This study identifies MDSCs as an essential component that provides protection against IMH following FTY720 or rapamycin treatment, validating the S1P1-mTOR signaling axis as a potential therapeutic target in hepatic injury.
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China;
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
authors.forename: Yujing
authors.initials: Y
authors.lastname: Bi
authors.forename: Ruoning
authors.initials: R
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Huanrong
authors.initials: H
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.forename: Zhengguo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Wanna
authors.initials: W
authors.lastname: Chen
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
authors.forename: Ruifu
authors.initials: R
authors.lastname: Yang
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D000068876:Fingolimod Hydrochloride; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology; D034622:RNA Interference; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D019707:Receptors, Chemokine; D049349:Receptors, Lysosphingolipid; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D020123:Sirolimus