期刊
BLOOD ADVANCES
卷 1, 期 14, 页码 947-960出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2017006858
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资金
- German Research Foundation [LU851/6-1, FZ82, SFB643 A6, GRK1660 A5]
- European Cooperation in Science and Technology program Mye-EUNITER
- Interdisciplinary Center for Clinical Research of the University Hospital Erlangen [A61]
Granulocyte-macrophage colony-stimulating factor (GM-CSF) controls proliferation and survival of myeloid cells including monocytes. Here, we describe a time-dependent licensing process driven by GM-CSF in murine Ly6C(high) and human CD14(+) monocytes that disables their inflammatory functions and promotes their conversion into suppressor cells. This 2-step licensing of monocytes requires activation of the AKT/mTOR/mTORC1 signaling cascade by GM-CSF followed by signaling through the interferon-gamma receptor (IFN-gamma R)/interferon regulatory factor-1 (IRF-1) pathway. Only licensing-dependent adaptations in Toll-like receptor/inflammasome, IFN-gamma R, and phosphatidylinositol 3-kinase/AKT/mTOR signaling lead to stabilized expression of inducible nitric oxide synthase by mouse and indoleamine 2,3-dioxygenase (IDO) by human monocytes, which accounts for their suppressor activity. This study suggests various myeloid cells with characteristics similar to those described for monocytic myeloid-derived suppressor cells, Mreg, or suppressor macrophages may arise from licensed monocytes. Markers of GM-CSF-driven monocyte licensing, including p-Akt, p-mTOR, and p-S6, distinguish inflammatory monocytes from potentially suppressive monocytes in peripheral blood of patients with high-grade glioma.
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