Anti-inflammatory Chromatinscape Suggests Alternative Mechanisms of Glucocorticoid Receptor Action

Summary

Despite the widespread use of glucocorticoids (GCs), their anti-inflammatory effects are not understood mechanistically. Numerous investigations have examined the effects of glucocorticoid receptor (GR) activation prior to inflammatory challenges. However, clinical situations are emulated by a GC intervention initiated in the midst of rampant inflammatory responses. To characterize the effects of a late GC treatment, we profiled macrophage transcriptional and chromatinscapes with Dexamethasone (Dex) treatment before or after stimulation by lipopolysaccharide (LPS). The late activation of GR had a similar gene expression profile as from GR pre-activation, while ameliorating the disruption of metabolic genes. Chromatin occupancy of GR was not predictive of Dex-regulated gene expression, contradicting the ‘trans-repression by tethering’ model. Rather, GR activation resulted in genome-wide blockade of NF-κB interaction with chromatin and directly induced inhibitors of NF-κB and AP-1. Our investigation using GC treatments with clinically relevant timing highlights mechanisms underlying GR actions for modulating the ‘inflamed epigenome’.

eTOC text

Although glucocorticoids are widely used anti-inflammatory drugs, relevant mechanisms are unclear. Oh et al. monitored the epigenomic landscape of macrophages, and found that the gene-inducing activity of GR is crucial for boosting inhibitors of inflammatory factors. This cautions the idea that GR ligands selectively promoting trans-repression should improve therapeutic outcome.