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Blood Adv. 2017 Jun 7;1(14):947-960. doi: 10.1182/bloodadvances.2017006858. eCollection 2017 Jun 13.

Novel GM-CSF signals via IFN-γR/IRF-1 and AKT/mTOR license monocytes for suppressor function.

Author information

1
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
2
Section of Experimental Surgery, Department of Surgery, University of Regensburg, Regensburg, Germany.
3
Rudolf Virchow Center, Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
4
Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
5
Microbiology Institute-Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
6
Stem Cell Laboratory, University Children's Hospital Würzburg, University of Würzburg, Würzburg, Germany; and.
7
Institute of Medical Microbiology and Hygiene, University of Marburg, Marburg, Germany.

Abstract

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 Ly6Chigh 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-γ receptor (IFN-γR)/interferon regulatory factor-1 (IRF-1) pathway. Only licensing-dependent adaptations in Toll-like receptor/inflammasome, IFN-γR, 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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