PMID- 25175012
OWN - NLM
STAT- MEDLINE
DCOM- 20151029
LR  - 20211203
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 5
DP  - 2014 Sep 1
TI  - TSC1 controls macrophage polarization to prevent inflammatory disease.
PG  - 4696
LID - 10.1038/ncomms5696 [doi]
AB  - Macrophages acquire distinct phenotypes during tissue stress and inflammatory 
      responses, but the mechanisms that regulate the macrophage polarization are 
      poorly defined. Here we show that tuberous sclerosis complex 1 (TSC1) is a 
      critical regulator of M1 and M2 phenotypes of macrophages. Mice with 
      myeloid-specific deletion of TSC1 exhibit enhanced M1 response and spontaneously 
      develop M1-related inflammatory disorders. However, TSC1-deficient mice are 
      highly resistant to M2-polarized allergic asthma. Inhibition of the mammalian 
      target of rapamycin (mTOR) fails to reverse the hypersensitive M1 response of 
      TSC1-deficient macrophages, but efficiently rescues the defective M2 
      polarization. Deletion of mTOR also fails to reverse the enhanced inflammatory 
      response of TSC1-deficient macrophages. Molecular studies indicate that TSC1 
      inhibits M1 polarization by suppressing the Ras GTPase-Raf1-MEK-ERK pathway in 
      mTOR-independent manner, whereas TSC1 promotes M2 properties by mTOR-dependent 
      CCAAT/enhancer-binding protein-beta pathways. Overall, these findings define a key 
      role for TSC1 in orchestrating macrophage polarization via mTOR-dependent and 
      independent pathways.
FAU - Zhu, Linnan
AU  - Zhu L
AD  - 1] State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of 
      Zoology, Chinese Academy of Sciences, Beijing 100101, China [2].
FAU - Yang, Tao
AU  - Yang T
AD  - 1] State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of 
      Zoology, Chinese Academy of Sciences, Beijing 100101, China [2].
FAU - Li, Longjie
AU  - Li L
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of 
      Zoology, Chinese Academy of Sciences, Beijing 100101, China.
FAU - Sun, Lina
AU  - Sun L
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of 
      Zoology, Chinese Academy of Sciences, Beijing 100101, China.
FAU - Hou, Yuzhu
AU  - Hou Y
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of 
      Zoology, Chinese Academy of Sciences, Beijing 100101, China.
FAU - Hu, Xuelian
AU  - Hu X
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of 
      Zoology, Chinese Academy of Sciences, Beijing 100101, China.
FAU - Zhang, Lianjun
AU  - Zhang L
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of 
      Zoology, Chinese Academy of Sciences, Beijing 100101, China.
FAU - Tian, Hongling
AU  - Tian H
AD  - Department of Oncology, The Affiliated Zhongshan Hospital of Dalian University, 
      Dalian 116001, China.
FAU - Zhao, Qingjie
AU  - Zhao Q
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of 
      Zoology, Chinese Academy of Sciences, Beijing 100101, China.
FAU - Peng, Jianxia
AU  - Peng J
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of 
      Zoology, Chinese Academy of Sciences, Beijing 100101, China.
FAU - Zhang, Hongbing
AU  - Zhang H
AD  - 1] National Laboratory of Medical Molecular Biology, Department of Physiology and 
      Pathophysiology, Institute of Basic Medical Sciences and School of Basic 
      Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, 
      Beijing 100005, China [2] Institute of Cancer Stem Cell, Dalian Medical 
      University, Dalian 116085, China.
FAU - Wang, Ruoyu
AU  - Wang R
AD  - Department of Oncology, The Affiliated Zhongshan Hospital of Dalian University, 
      Dalian 116001, China.
FAU - Yang, Zhongzhou
AU  - Yang Z
AD  - MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research 
      Center, Nanjing University, Nanjing 210093, China.
FAU - Zhang, Lianfeng
AU  - Zhang L
AD  - Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, 
      Institute of Laboratory Animal Science, CAMS &PUMC, Beijing 100021, China.
FAU - Zhao, Yong
AU  - Zhao Y
AD  - State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of 
      Zoology, Chinese Academy of Sciences, Beijing 100101, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140901
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (CCAAT-Enhancer-Binding Protein-beta)
RN  - 0 (Cebpb protein, mouse)
RN  - 0 (TSC1 protein, human)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 0 (ras GTPase-Activating Proteins)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - Tuberous Sclerosis 1
SB  - IM
MH  - Animals
MH  - Asthma/*genetics/immunology/pathology
MH  - CCAAT-Enhancer-Binding Protein-beta/genetics/immunology
MH  - Cell Differentiation
MH  - Cell Lineage/immunology
MH  - Female
MH  - Gene Expression Regulation
MH  - MAP Kinase Signaling System
MH  - Macrophages/*immunology/pathology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Proto-Oncogene Proteins c-raf/genetics/immunology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*genetics/immunology
MH  - Tuberous Sclerosis/*genetics/immunology/pathology
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tumor Suppressor Proteins/deficiency/*genetics/immunology
MH  - ras GTPase-Activating Proteins/genetics/immunology
EDAT- 2014/09/02 06:00
MHDA- 2015/10/30 06:00
CRDT- 2014/09/02 06:00
PHST- 2014/06/02 00:00 [received]
PHST- 2014/07/15 00:00 [accepted]
PHST- 2014/09/02 06:00 [entrez]
PHST- 2014/09/02 06:00 [pubmed]
PHST- 2015/10/30 06:00 [medline]
AID - ncomms5696 [pii]
AID - 10.1038/ncomms5696 [doi]
PST - epublish
SO  - Nat Commun. 2014 Sep 1;5:4696. doi: 10.1038/ncomms5696.