mTOR signaling disruption from myeloid-derived suppressive cells protects against immune-mediated hepatic injury through the HIF1α-dependent glycolytic pathway

Journal of Leukocyte Biology

Yujing Bi⁵  Zan Fu⁶  Pingsheng Gong⁴  Xi Chen, ³  Anna Jia²  Jian Wang³  Lixiang Xue–⁷  Qing Yu²  Zhengguo Zhang, ³  Guangwei Liu, ,4³  Hui Yang,3 and¹  Yan Li³ 

[1] 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;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;Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun, China;State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing China;Division of Colorectal Surgery, Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing China;–Medical Research Center, Department of Radiation Oncology, Peking University Third Hospital, Beijing, China Department of Immunology, School of Basic Medical Science, Fudan University, Shanghai China;

关键词: hepatitis;    T_H1 cells;    T_regs;    T cell differentiation;    innate immunity;   

DOI  :  10.1189/jlb.2A1115-492R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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+ Tregs. Mechanistically, 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.

【 授权许可】

Unknown