title: mTOR limits the recruitment of CD11b+Gr1+Ly6Chigh myeloid-derived suppressor cells in protecting against murine immunological hepatic injury.
abstract: The mTOR pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct the innate and adaptive immune responses. 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 unknown. Here, we show that mTOR signaling is a pivotal negative determinant of MDSC recruitment in IMH disease. In the context of IMH, inhibition of mTOR with rapamycin in CD11b⁺Gr1⁺ MDSCs mediates protection against IMH and serves as a functional, suppressive immune modulator that results in increased CD11b⁺Gr1⁺Ly6C(high) MDSC recruitment to inflammatory sites. In agreement with this, mTOR down-regulation promotes CD11b⁺Gr1⁺Ly6C(high) MDSC migration in vitro and in vivo. Mechanistically, mTOR activity down-regulation in MDSCs induced iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated MDSC recruitment. This study identifies MDSCs as an essential component for protection against IMH following rapamycin treatment. Rapamycin treatment or mTOR inhibition promotes CD11b⁺Gr1⁺Ly6C(high) MDSC recruitment and is critically required for protection against hepatic injury. This study further validates the targeting of mTOR signaling as a potential therapeutic approach to IMH-related diseases.
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, Fudan University, Shanghai, China; and.
authors.forename: Yan
authors.initials: Y
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: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, and Biotherapy Research Center, Fudan University, Shanghai, China; 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, Fudan University, Shanghai, China; 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, Fudan University, Shanghai, China; 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, Fudan University, Shanghai, China; 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, Fudan University, Shanghai, China; 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, Fudan University, Shanghai, China; 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, Fudan University, Shanghai, China; and.
authors.forename: Shan
authors.initials: S
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, Fudan University, Shanghai, China; and.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Ruifu
authors.initials: R
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, Fudan University, Shanghai, China; and liugw@fudan.edu.cn.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000032:analysis*; D039481:CD11b Antigen / Q000032:analysis*; D002465:Cell Movement / Q000187:drug effects; D007108:Immune Tolerance; D008107:Liver Diseases / Q000276:immunology*; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000032:analysis*; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; C526827:Ly6 protein, mouse; D019707:Receptors, Chemokine; D009569:Nitric Oxide; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: autoimmune; cell migration; immune defense; inflammation; inflammatory cell infiltration