PMID- 27462101
OWN - NLM
STAT- MEDLINE
DCOM- 20170906
LR  - 20211204
IS  - 1938-3673 (Electronic)
IS  - 0741-5400 (Linking)
VI  - 100
IP  - 6
DP  - 2016 Dec
TI  - mTOR signaling disruption from myeloid-derived suppressive cells protects against 
      immune-mediated hepatic injury through the HIF1alpha-dependent glycolytic pathway.
PG  - 1349-1362
AB  - 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-gamma-producing T(H)1 cells and more Foxp3(+) 
      T(regs) 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, HIF1alpha-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.
CI  - (c) Society for Leukocyte Biology.
FAU - Chen, Xi
AU  - Chen X
AD  - Department of Immunology, School of Basic Medical Science, Fudan University, 
      Shanghai China.
AD  - 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.
FAU - Zhang, Zhengguo
AU  - Zhang Z
AD  - Department of Immunology, School of Basic Medical Science, Fudan University, 
      Shanghai China.
AD  - 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.
FAU - Bi, Yujing
AU  - Bi Y
AD  - State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of 
      Microbiology and Epidemiology, Beijing China.
FAU - Fu, Zan
AU  - Fu Z
AD  - Division of Colorectal Surgery, Department of General Surgery, First Affiliated 
      Hospital of Nanjing Medical University, Nanjing China.
FAU - Gong, Pingsheng
AU  - Gong P
AD  - Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education, 
      Jilin University, Changchun, China.
FAU - Li, Yan
AU  - Li Y
AD  - Department of Immunology, School of Basic Medical Science, Fudan University, 
      Shanghai China.
AD  - 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.
FAU - Yu, Qing
AU  - Yu Q
AD  - 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.
FAU - Jia, Anna
AU  - Jia A
AD  - 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.
FAU - Wang, Jian
AU  - Wang J
AD  - Department of Immunology, School of Basic Medical Science, Fudan University, 
      Shanghai China.
AD  - 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.
FAU - Xue, Lixiang
AU  - Xue L
AD  - Medical Research Center, Department of Radiation Oncology, Peking University 
      Third Hospital, Beijing, China lixiangxue@bjmu.edu.cn.
FAU - Yang, Hui
AU  - Yang H
AD  - Department of Immunology, School of Basic Medical Science, Fudan University, 
      Shanghai China; huiyang@fudan.edu.cn.
FAU - Liu, Guangwei
AU  - Liu G
AD  - Department of Immunology, School of Basic Medical Science, Fudan University, 
      Shanghai China; liugw@bnu.edu.cn.
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20160726
PL  - England
TA  - J Leukoc Biol
JT  - Journal of leukocyte biology
JID - 8405628
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 11028-71-0 (Concanavalin A)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adoptive Transfer
MH  - Animals
MH  - Concanavalin A/administration & dosage/toxicity
MH  - Dose-Response Relationship, Immunologic
MH  - Female
MH  - Glycolysis/*physiology
MH  - Hepatitis, Autoimmune/drug therapy/etiology/immunology/*prevention & control
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/genetics/*physiology
MH  - Lymphocyte Activation/drug effects
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Myeloid-Derived Suppressor Cells/*immunology/transplantation
MH  - Nitric Oxide/physiology
MH  - RNA Interference
MH  - Recombinant Fusion Proteins/metabolism
MH  - Signal Transduction
MH  - Sirolimus/pharmacology/therapeutic use
MH  - Specific Pathogen-Free Organisms
MH  - T-Lymphocyte Subsets/immunology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*physiology
OTO - NOTNLM
OT  - T cell differentiation
OT  - TH1 cells
OT  - Tregs
OT  - hepatitis
OT  - innate immunity
EDAT- 2016/07/28 06:00
MHDA- 2017/09/07 06:00
CRDT- 2016/07/28 06:00
PHST- 2015/11/02 00:00 [received]
PHST- 2016/06/07 00:00 [revised]
PHST- 2016/06/27 00:00 [accepted]
PHST- 2016/07/28 06:00 [pubmed]
PHST- 2017/09/07 06:00 [medline]
PHST- 2016/07/28 06:00 [entrez]
AID - jlb.2A1115-492R [pii]
AID - 10.1189/jlb.2A1115-492R [doi]
PST - ppublish
SO  - J Leukoc Biol. 2016 Dec;100(6):1349-1362. doi: 10.1189/jlb.2A1115-492R. Epub 2016 
      Jul 26.