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Autophagy. 2019 Jul;15(7):1150-1162. doi: 10.1080/15548627.2019.1578040. Epub 2019 Feb 27.

The MTOR signaling pathway regulates macrophage differentiation from mouse myeloid progenitors by inhibiting autophagy.

Author information

1
a Department of Radiation Oncology, Shanghai Ninth People's Hospital , Shanghai Jiaotong University School of Medicine , Shanghai , China.
2
b Department of Oncology, Shanghai Ninth People's Hospital , Shanghai Jiaotong University School of Medicine , Shanghai , China.
3
c Department of Chemotherapy , Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province , Nanjing , Jiangsu , China.
4
d State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital , Chinese Academy of Medical Sciences & Peking Union Medical College , Tianjin , China.
5
e Department of Cell and Developmental Biology , University of Illinois at Urbana-Champaign , Urbana , IL , USA.
6
f Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital , Shanghai JiaoTong University School of Medicine , Shanghai , China.

Abstract

Understanding of the mechanism for myeloid differentiation provides important insights into the hematopoietic developmental processes. By using an ESC-derived myeloid progenitor cell model, we found that CSF2/GM-CSF triggered macrophage differentiation and activation of the MTOR signaling pathway. Activation or inhibition of the MTOR signaling enhanced or attenuated macrophage differentiation, respectively, suggesting a critical function. We further showed that macroautophagy/autophagy was inhibited with the addition of CSF2. Furthermore, pharmacological inhibition and genetic modification of autophagy enhanced macrophage differentiation and rescued the inhibitory effect on differentiation caused by MTOR inhibition. Thus, the MTOR signaling pathway regulates macrophage differentiation of myeloid progenitors by inhibiting autophagy. Our results provide new insights into the mechanisms for myeloid differentiation and may prove useful for therapeutic applications of hematopoietic and myeloid progenitor cells. Abbreviations: 2-DG: 2-deoxy-D-glucose; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; BM: bone marrow; CQ: chloroquine; ECAR: extracellular acidification rate; ESC: embryonic stem cell; CSF2/GM-CSF: colony stimulating factor 2; CSF3/G-CSF: colony stimulating factor 3; HPC: hematopoietic progenitor cell; ITGAM/CD11b: integrin alpha M; LPS: lipopolysaccharide; MFI: median fluorescence intensity; MTOR: mechanistic target of rapamycin kinase; RPS6KB1/p70S6K1: ribosomal protein S6 kinase, polypeptide 1; shRNA: short hairpin RNA; SQSTM1/p62: sequestosome 1.

KEYWORDS:

Autophagy; CSF2; MTOR; myeloid differentiation; myeloid progenitors

PMID:
30724690
PMCID:
PMC6613836
[Available on 2020-02-27]
DOI:
10.1080/15548627.2019.1578040

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