TSC1 controls macrophage polarization to prevent inflammatory disease

Linnan Zhu, Tao Yang, Longjie Li, Lina Sun, Yuzhu Hou, Xuelian Hu, Lianjun Zhang, Hongling Tian, Qingjie Zhao, Jianxia Peng, Hongbing Zhang, Ruoyu Wang, Zhongzhou Yang, Lianfeng Zhang and Yong Zhao ()
Additional contact information
Linnan Zhu: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences
Tao Yang: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences
Longjie Li: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences
Lina Sun: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences
Yuzhu Hou: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences
Xuelian Hu: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences
Lianjun Zhang: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences
Hongling Tian: The Affiliated Zhongshan Hospital of Dalian University
Qingjie Zhao: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences
Jianxia Peng: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences
Hongbing Zhang: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College
Ruoyu Wang: The Affiliated Zhongshan Hospital of Dalian University
Zhongzhou Yang: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University
Lianfeng Zhang: Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, CAMS & PUMC
Yong Zhao: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract 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-β pathways. Overall, these findings define a key role for TSC1 in orchestrating macrophage polarization via mTOR-dependent and independent pathways.

Date: 2014
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DOI: 10.1038/ncomms5696

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