title: mTOR signaling disruption from myeloid-derived suppressive cells protects against immune-mediated hepatic injury through the HIF1α-dependent glycolytic pathway.
abstract: The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct innate and adaptive immune responses. Myeloid-derived suppressive cells (MDSCs) are a heterogeneous cell population that plays a crucial regulatory effect in immune-related diseases. However, whether mTOR signaling affects the functions of MDSCs remains largely unexplored. Here, we show that mTOR signaling is a pivotal, negative determinant of MDSC function in immune-mediated hepatic injury (IMH) diseases. In the context of IMH, the blocking of mTOR with rapamycin or mTOR-deficient CD11b+Gr1+MDSCs mediates the protection against IMH; mTOR with rapamycin and mTOR-deficient CD11b+Gr1+MDSCs are suppressive immune modulators that result in less IFN-γ-producing TH1 cells and more Foxp3+TregsMechanistically, mTOR activity down-regulation in MDSCs induced iNOS expressions and NO productions. Pharmacologic inhibitions of iNOS completely eliminate MDSC-suppressive function and lose their inducible effects on T cell differentiation. Importantly, HIF1α-dependent glycolytic activity is responsible for mTOR-deficient, increased MDSC functional changes in IMH inflammation. Thus, these data demonstrate that mTOR acts as a fundamental "rheostat" in MDSCs to link immunologic signals to glycolytic pathways and functional fitness and highlights a central role of metabolic programming of MDSC-suppressive activity in protecting against immune hepatic injuries.
authors.affiliation: Department of Immunology, School of Basic Medical Science, Fudan University, 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, Beijing China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Immunology, School of Basic Medical Science, Fudan University, 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, Beijing China.
authors.forename: Zhengguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Division of Colorectal Surgery, Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun, China.
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Gong
authors.affiliation: Department of Immunology, School of Basic Medical Science, Fudan University, 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, Beijing China.
authors.forename: Yan
authors.initials: Y
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, Beijing China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
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, Beijing China.
authors.forename: Anna
authors.initials: A
authors.lastname: Jia
authors.affiliation: Department of Immunology, School of Basic Medical Science, Fudan University, 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, Beijing China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Medical Research Center, Department of Radiation Oncology, Peking University Third Hospital, Beijing, China lixiangxue@bjmu.edu.cn.
authors.forename: Lixiang
authors.initials: L
authors.lastname: Xue
authors.affiliation: Department of Immunology, School of Basic Medical Science, Fudan University, Shanghai China; huiyang@fudan.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Immunology, School of Basic Medical Science, Fudan University, Shanghai China; liugw@bnu.edu.cn.|Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing China.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D003208:Concanavalin A / Q000008:administration & dosage / Q000633:toxicity; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006019:Glycolysis / Q000502:physiology*; D019693:Hepatitis, Autoimmune / Q000188:drug therapy / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology* / Q000637:transplantation; D009569:Nitric Oxide / Q000502:physiology; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011993:Recombinant Fusion Proteins; D003208:Concanavalin A; D009569:Nitric Oxide; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: T cell differentiation; TH1 cells; Tregs; hepatitis; innate immunity