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

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.