Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells

Georg Varga^*^,^,1, Jan Ehrchen^*^,^,1, Athanasios Tsianakas^*^,, Klaus Tenbrock^*^,, Anke Rattenholl, Stephan Seeliger, Matthias Mack, Johannes Roth^*^, and Cord Sunderkoetter^*^,^,2

^* Institute of Immunology and Departments of
Dermatology and
Pediatrics, University of Muenster, Muenster, Germany; and
Department of Internal Medicine II, University Hospital of Regensburg, Regensburg, Germany

² Correspondence: Department of Dermatology, University of Muenster, Von Esmarch Str. 58, Muenster D-48149, Germany. E-mail: cord.sunderkoetter{at}ukmuenster.de

ABSTRACT

Glucocorticoids (GC) are still the most widely used immunosuppressiveagents in clinical medicine. Surprisingly, little is known aboutthe mechanisms of GC action on monocytes, although these cellsexert pro- and anti-inflammatory effects. We have shown recentlythat GC induce a specific monocyte phenotype with anti-inflammatoryproperties in humans. We now investigated whether this alsoapplies for the murine system and how this subset would relateto recently defined murine subtypes. After treatment with dexamethasonefor 48 h, monocytes up-regulated scavenger receptor CD163 andGr-1, down-regulated CX₃CR1, and shared with human GC-treatedmonocytes functional features such as low adhesiveness but highmigratory capacity. They specifically up-regulated anti-inflammatoryIL-10, but not TGF-β, and in contrast to their human counterparts,they down-regulated IL-6. Although GC-induced monocytes down-regulatedCX₃CR1, a distinctive marker for classical/proinflammatory humanand murine monocytes (CX₃CR1^loCCR2⁺Ly6C^hi), they differed fromthis physiologically occurring subset, as they remained Ly6C^medand unactivated (CD62 ligand⁺⁺). In addition to their immunosuppressiveeffects, they were CD11b⁺Gr-1⁺ and expressed the IL-4R ${alpha}$ chain(CD124), a recently described, signature molecule of tumor-inducedmyeloid-derived suppressor cells (MDSC). We therefore generatedmurine MDSC in B16 melanoma-bearing mice and indeed found parallelup-regulation of CD11b⁺Gr-1⁺ and CD124 on GC-induced monocytesand MDSC. These data allow us to speculate that the GC-inducedsubtype shares with inflammatory monocytes the ability to migratequickly into inflamed tissue, where they, however, exert anti-inflammatoryeffects and that similarities between GC-induced monocytes andMDSC may be involved in progression of some tumors observedin patients chronically treated with GC.

Key Words: IL-10 • CD124