title: Glucocorticoid receptor promotes the function of myeloid-derived suppressor cells by suppressing HIF1α-dependent glycolysis.
abstract: Immunomodulatory signaling imposes tight regulations on metabolic programs within immune cells and consequentially determines immune response outcomes. Although the glucocorticoid receptor (GR) has been recently implicated in regulating the function of myeloid-derived suppressor cells (MDSCs), whether the dysregulation of GR in MDSCs is involved in immune-mediated hepatic diseases and how GR regulates the function of MDSCs in such a context remains unknown. Here, we revealed the dysregulation of GR expression in MDSCs during innate immunological hepatic injury (IMH) and found that GR regulates the function of MDSCs through modulating HIF1α-dependent glycolysis. Pharmacological modulation of GR by its agonist (dexamethasone, Dex) protects IMH mice against inflammatory injury. Mechanistically, GR signaling suppresses HIF1α and HIF1α-dependent glycolysis in MDSCs and thus promotes the immune suppressive activity of MDSCs. Our studies reveal a role of GR-HIF1α in regulating the metabolism and function of MDSCs and further implicate MDSC GR signaling as a potential therapeutic target in hepatic diseases that are driven by innate immune cell-mediated systemic inflammation.
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.|Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.|Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
authors.forename: Huanrong
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 100071, Beijing, China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.|Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.|Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.|Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
authors.forename: Zhengguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.|Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.|Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
authors.forename: Anna
authors.initials: A
authors.lastname: Jia
authors.affiliation: Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
authors.forename: Linian
authors.initials: L
authors.lastname: Han
authors.affiliation: Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China. zhaoy@ioz.ac.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Hematology/Oncology and BMT, The Research Institute at Nationwide Children's Hospital, Ohio State University, 43205, Columbus, USA, Ohio. zhaoy@ioz.ac.cn.
authors.forename: Ruoning
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China. zhaoy@ioz.ac.cn.|Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, 100875, Beijing, China. zhaoy@ioz.ac.cn.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007108:Immune Tolerance / Q000187:drug effects; D007113:Immunity, Innate; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides; D008099:Liver / Q000293:injuries / Q000473:pathology; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone