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mTOR masters monocyte development in bone marrow by decreasing the inhibition of STAT5 on IRF8

Yang Zhao, Xiaofei Shen, Ning Na, Zhulang Chu, Huiting Su, Shanshan Chao, Lu Shi, Yanan Xu, Lianfeng Zhang, Bingyi Shi and Yong Zhao

Key points

  • mTOR intrinsically controls monocyte/macrophage development in the early stage.

  • mTOR masters monocyte development via STAT5-IRF8-CD115 pathway.

Abstract

Monocytes and macrophages play a key role in defending pathogens, removing the dead cells or cell debris and wound healing. mTOR inhibitor, rapamycin (RPM) is widely used in clinics to treat patients with organ transplantation or tumors. The role of mTOR in monocyte/macrophage development remains to be clarified. Herein we found that mTOR intrinsically controls monocyte/macrophage development as evidenced by the decreased percentages and cell numbers of CD11b+F4/80+ cells caused by mTOR inhibition in SCID mice, mTOR-deficient mice, mixed chimera mice and the in vitro colony formation and monocyte/macrophage induction assays. However, the Lyzs-mTOR KO mice displayed normal levels of monocytes/macrophages, indicating that mTOR is not essential for the survival and maturation of monocytes/macrophages. Further studies showed that mTOR deficiency significantly reduced M-CSF receptor CD115 expression at the transcriptional and translational levels. The molecular mechanism studies indicate that the impaired monocyte/macrophage development caused by mTOR deficiency mainly due to the over-activated STAT5 and subsequent down-regulation of IRF8 but not the altered cell metabolism and autophagy. Therefore, our work identifies that mTOR is an intrinsic master for monocyte/macrophage development at the early stages through regulating STAT5-IRF8-dependent CD115 expressing pathway. Long term usage of RPM may cause defect of myeloid progenitors in bone marrow.

  • Submitted April 4, 2017.
  • Accepted January 31, 2018.