title: Dexamethasone potentiates myeloid-derived suppressor cell function in prolonging allograft survival through nitric oxide.
abstract: Whereas GCs have been demonstrated to be beneficial for transplantation patients, the pharmacological mechanisms remain unknown. Herein, the role of GR signaling was investigated via a pharmacological approach in a murine allogeneic skin transplantation model. The GC Dex, a representative GC, significantly relieved allograft rejection. In Dex-treated allograft recipient mice, CD11b(+)Gr1(+) MDSCs prolonged graft survival and acted as functional suppressive immune modulators that resulted in fewer IFN-γ-producing Th1 cells and a greater number of IL-4-producing Th2 cells. In agreement, Dex-treated MDSCs promoted reciprocal differentiation between Th1 and Th2 in vivo. Importantly, the GR is required in the Dex-induced MDSC effects. The blocking of GR with RU486 significantly diminished the expression of CXCR2 and the recruitment of CD11b(+)Gr1(+) MDSCs, thereby recovering the increased MDSC-suppressive activity induced by Dex. Mechanistically, Dex treatment induced MDSC iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated the MDSC-suppressive function and the effects on T cell differentiation. This study shows MDSCs to be an essential component in the prolongation of allograft survival following Dex or RU486 treatment, validating the GC-GR-NO signaling axis as a potential therapeutic target in transplantation.
authors.affiliation: Ruijin Hospital and Medical School of Shanghai Jiao Tong University, Shanghai, China; Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
authors.forename: Jiongbo
authors.initials: J
authors.lastname: Liao
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China; and.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China;
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.affiliation: Ruijin Hospital and Medical School of Shanghai Jiao Tong University, Shanghai, China; Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
authors.forename: Kun
authors.initials: K
authors.lastname: Shao
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
authors.forename: Zhengguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
authors.forename: Huanrong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University, Health Science Center, Beijing, China liugw@fudan.edu.cn wxh@medmail.com.cn lixiangxue@bjmu.edu.cn.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Xue
authors.affiliation: Ruijin Hospital and Medical School of Shanghai Jiao Tong University, Shanghai, China; liugw@fudan.edu.cn wxh@medmail.com.cn lixiangxue@bjmu.edu.cn.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Institute of Immunobiology, and liugw@fudan.edu.cn wxh@medmail.com.cn lixiangxue@bjmu.edu.cn.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
mesh_terms: D064591:Allografts / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism; D016038:Skin Transplantation; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D039481:CD11b Antigen; D011956:Receptors, Cell Surface; C551746:granulocyte receptor 1, mouse; D009569:Nitric Oxide; D003907:Dexamethasone
keywords: Th1 cells; Tregs; glucocorticoids; graft rejection; innate immunity; tolerance