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

Abstract

Glucocorticoids (GC) are still the most widely used immunosuppressive agents in clinical medicine. Surprisingly, little is known about the mechanisms of GC action on monocytes, although these cells exert pro- and anti-inflammatory effects. We have shown recently that GC induce a specific monocyte phenotype with anti-inflammatory properties in humans. We now investigated whether this also applies for the murine system and how this subset would relate to recently defined murine subtypes. After treatment with dexamethasone for 48 h, monocytes up-regulated scavenger receptor CD163 and Gr-1, down-regulated CX(3)CR1, and shared with human GC-treated monocytes functional features such as low adhesiveness but high migratory capacity. They specifically up-regulated anti-inflammatory IL-10, but not TGF-beta, and in contrast to their human counterparts, they down-regulated IL-6. Although GC-induced monocytes down-regulated CX(3)CR1, a distinctive marker for classical/proinflammatory human and murine monocytes (CX(3)CR1(lo)CCR2(+)Ly6C(hi)), they differed from this physiologically occurring subset, as they remained Ly6C(med) and unactivated (CD62 ligand(++)). In addition to their immunosuppressive effects, they were CD11b(+)Gr-1(+) and expressed the IL-4Ralpha chain (CD124), a recently described, signature molecule of tumor-induced myeloid-derived suppressor cells (MDSC). We therefore generated murine MDSC in B16 melanoma-bearing mice and indeed found parallel up-regulation of CD11b(+)Gr-1(+) and CD124 on GC-induced monocytes and MDSC. These data allow us to speculate that the GC-induced subtype shares with inflammatory monocytes the ability to migrate quickly into inflamed tissue, where they, however, exert anti-inflammatory effects and that similarities between GC-induced monocytes and MDSC may be involved in progression of some tumors observed in patients chronically treated with GC.

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…16 Here we confirm these findings and show that HLA-DR/DP/DQ loss in Dex-treated patients is independent of disease grade (Figure 6A). Consistent with the fact that the gene for CD163 is glucocorticoid-regulated, 18,22,29 we found that CD163 was expressed on a higher percentage of circulating CD14+ monocytes in Dex-treated low and high-grade glioma patients (Figure 6B). In contrast, we see no change in the frequency of the commonly used MDSC marker CD33 (Figure 6C) or the T cell suppressive marker PD-L1 (Figure 6D), indicating that Dex doesn’t universally suppress surface protein expression, but may have specific targets.…”

“…14 Although glucocorticoid signaling increases expression of CD163 on myeloid cells, 22,29 the effects on accumulation of CD163+ cells in tumor tissue are less well understood. Recent work suggests that variation in the expression of macrophage immune modulatory proteins is more critical to disease progression than macrophage accumulation within the tumor.…”

α1-Acid Glycoprotein Up-regulates CD163 via TLR4/CD14 Protein Pathway

“…For example, a genomic analysis of the CD163 promoter region revealed the presence of several binding sites for transcription factors in the 5Ј-flanking region (45), including three putative glucocorticoid receptor binding sites. In fact, monocytes that had been treated with glucocorticoids or derived from patients on glucocorticoid pulse therapy showed a strongly induced CD163 expression (12,15,46,47). Taking the collective findings into consideration, with the evidence that glucocorticoid also up-regulates AGP synthesis (20), glucocorticoids might not only regulate CD163 expression directly but also indirectly via enhancing AGP production.…”

The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in the inflammatory response

“…The latter group are notable for their "deactivated" phenotype, migrating to sites of infection where they have an enhanced ability to clear debris and apoptotic cells by a non-phlogistic mechanism (Ren et al, 2001) which is, in turn, stimulated by glucocorticoids , thus actively contributing to the resolution of inflammation (Savill et al, 2002). Intriguingly, it has recently been reported that the anti-inflammatory monocytes induced by glucocorticoids resemble myeloid-derived suppressor cells, a finding with implications for tumour progression under conditions of glucocorticoid excess (Varga et al, 2008).…”

“…During inflammation, predominantly a response of the innate immune system, glucocorticoids restrain oedema, increase blood viscosity and alter leukocyte distribution/trafficking, haematopoietic differentiation programmes and gene transcription . Importantly, they also promote the resolution of inflammation by inducing an anti-inflammatory phenotype in differentiating monocytes (Ehrchen et al, 2007;Giles et al, 2001;Varga et al, 2008), promoting survival of anti-inflammatory macrophages (Mφ) during inflammation and increasing non-phlogistic phagocytosis of apoptotic neutrophils by Mφ (reviewed (Heasman et al, 2003;Yona and Gordon, 2007)). Endogenous glucocorticoid activity depends upon glucocorticoid output from the adrenal gland, under the control of the hypothalamic-pituitary-adrenal (HPA) axis and indeed, infection or trauma is a potent stimulus to the HPA axis (Sternberg, 2001).…”