Inflammation: Glucocorticoids turn the monocyte switch

Glucocorticoids (GCs) play a central role in regulating homeostatic mechanisms associated with metabolic control and inflammation. Surprisingly, the specific anti-inflammatory effects of GCs on different cells of the immune system remain poorly understood. In a recent study, Ehrchen et al.1 have shown that GCs increase migration of anti-inflammatory monocytes to sites of infection where they have an enhanced ability to clear debris without giving rise to inflammation. Fifty years after GCs were initially used in the treatment of inflammatory diseases,2 they are still among the most potent drugs in clinical use today, despite their unwelcome side effects. GCs suppress inflammation in a wide array of disorders, including asthma, rheumatoid arthritis and inflammatory bowel disease. In the United Kingdom, it is estimated that over 250 000 patients receive continuous oral GC therapy.3 The literature has described important advances in our understanding of how these drugs suppress inflammation. However, the precise phenotypic effects of these drugs on monocytes remain elusive. As we enter the postgenomic era, gene expression profiles provide insights into the functional changes that underlie macrophage (MØ) heterogeneity. Monocytes originate in the bone marrow from common myeloid progenitors and are released into the peripheral circulation. Constitutive, proinflammatory, metabolic and immune stimuli result in the recruitment of monocytes to peripheral sites where they differentiate into tissue MØs, inflammatory MØs and myeloid dendritic cells. These cells contribute to host defence and tissue remodelling. As a result of cellular differentiation in different tissue microenvironments, mononuclear phagocytes display marked phenotypic heterogeneity, reflecting the specialization of individual MØ populations. Specific cytokines acting alone or in combination induce their own unique patterns of gene expression during mononuclear phagocyte activation (Figure 1). Canonically activated MØs develop during the immune response to interferon-γ (IFN-γ) and concomitant exposure to microbial products, for example lipopolysaccharide (LPS).4 Hallmarks of such T helper 1 (TH1)-type activation include increased secretion of proinflammatory cytokines, enhanced expression of selected receptor functions and microbial killing, whereas alternatively activated MØs are generated during TH2-type responses. Exposure to interleukin-4 (IL-4) and IL-13 yields MØs with a distinctive phenotype, implicated in allergic and parasitic inflammation. Excessive MØ activation is limited by IL-10, transforming growth factor β (TGFβ) or GCs, which induce their own specific patterns of gene expression. The mechanisms of GC actions on monocytes and their contribution to systemic anti-inflammatory effects remain unclear. GCs inhibit both early and late manifestations of acute inflammation and modulate subsequent repair. Transcriptional effects of GCs on monocytes have been described as slow, occurring over a period of hours, as would be predicted under physiological concentrations of GCs. The GC receptor (GR) heterodimer binds to DNA at the glucocorticoid response elements, upstream of the promoter regions of GC-responsive genes, inducing or repressing transcription,5 thus generating monocytes with broad anti-inflammatory and pro-resolution properties. The experiments conducted by Ehrchen et al.1 recently published in the journal, Blood, have added to our understanding of how these drugs programme an anti-inflammatory monocyte phenotype. Transcription expression profiles were generated following stimulation of monocytes for 18 h with fluticasone, a new generation GC with a higher binding affinity to the GR than previous drugs. GCs modulate the expression of ∼130 genes over this short time frame, including the expression of anti-inflammatory genes involved in chemotaxis, phagocytosis and antioxidative stress while suppressing pro-inflammatory genes involved in apoptosis, adhesion and T-cell chemotaxis. An array of genes known to be upregulated by IFNγ, for example the T-cell chemokines CXCL10, CXCL11, CCL5 and CCL24, are downregulated. GCs increase expression of IL-10 and other anti-inflammatory molecules, for example the decoy receptor IL-1RII and Delta sleep inactivating peptide (DSIP), an inhibitor of NF-κB activation. Thus, GCs induce a distinctive signature of monocyte gene expression, which may account for some of their potent anti-inflammatory actions in vivo. Another molecule regulated by GCs is formyl-peptide receptor-like 1 (FPR-L1),6 a receptor for the anti-inflammatory mediators Annexin A1 and Lipoxin A4.7 Ehrchen et al. demonstrate the upregulation by GCs of another member of the FPR family, FPR1. The observation of fMLP-mediated migration following GC incubation may explain, in part, why FPR1 and FPR-L1 ligation dampen inflammatory responses. Ligation of both the FPR1 and FPR-L1 is known to suppress pro-inflammatory cytokine secretion in response to bacterial stimuli, yet enhancing the resolution of inflammation.8,9,10 GCs are known to hasten apoptotic neutrophil clearance.11 Uptake of apoptotic neutrophils by MØs, in contrast to other phagocytic processes, inhibits the release of pro-inflammatory cytokines during the resolution of inflammation.12 Clearance by MØ is mediated partly by increased expression of the GC-regulated protein annexin A1.8 Ehrchen et al. report that GCs increase expression of monocyte genes known to be associated with apoptotic cell phagocytosis, including MFGE8, MERTK and C1QA. In addition to enhancing the clearance of apoptotic neutrophils, GCs also enhance bacterial phagocytosis1,13 in a non-phlogistic manner. Increased expression of the pro-inflammatory haptoglobin–haemoglobin clearance receptor CD16314 and stabilin-1,15 a selective transporter that regulates physiological clearance of modified self and non-self compounds, have been shown to be regulated by GCs. Ehrchen et al. only demonstrated the transcriptional modulation of GCs on monocytes over a short time course and hypothesize that GCs increase the migration of anti-inflammatory monocytes with enhanced clearance properties at the sites of infection. It will be interesting to see how GCs modulate transcription over a longer time period in vitro and to what extent the effects of monocytes contribute to GC actions in vivo. The relative importance of genomic versus non-genomic contributions exerted by GCs has been widely debated. Many GC anti-inflammatory actions cannot be attributed to transcription alone. For example, the rapid response of patients with acute adrenal insufficiency,16 the rapid inhibition of ACTH release17 and the rapid activation of eNOS, protecting patients from ischaemia or reperfusion injury,18 are evident within minutes of GC administration. Therefore, GCs can also influence cellular responses without induction of transcriptional/translational processes. Monocytes undergo distinctive pathways of differentiation in response to different cytokines and GCs. Some of the characteristic effects on cellular phenotype are shown. For further information, see reference.4