Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor

Abstract

For many decades, glucocorticoids have been widely used as the gold standard treatment for inflammatory conditions. Unfortunately, their clinical use is limited by severe adverse effects such as insulin resistance, cardiometabolic diseases, muscle and skin atrophies, osteoporosis, and depression. Glucocorticoids exert their effects by binding to the Glucocorticoid Receptor (GR), a ligand-activated transcription factor which both positively, and negatively regulates gene expression. Extensive research during the past several years has uncovered novel mechanisms by which the GR activates and represses its target genes. Genome-wide studies and mouse models have provided valuable insight into the molecular mechanisms of inflammatory gene regulation by GR. This review focusses on newly identified target genes and GR co-regulators that are important for its anti-inflammatory effects in innate immune cells, as well as mutations within the GR itself that shed light on its transcriptional activity. This research progress will hopefully serve as the basis for the development of safer immune suppressants with reduced side effect profiles.

Keywords: gene regulation; glucocorticoid receptor; inflammation; macrophages; mouse models.

Figure 1

Overview of the glucocorticoid receptor protein. The Glucocorticoid Receptor (GR) is organized into three main domains: the N-terminal Transactivation Domain (NTD), the DNA-Binding Domain (DBD), and the Ligand Binding Domain (LBD). In addition, there are the transactivation domains 1 and 2 (AF-1 and AF-2). These mutations numbered above are relevant for GR's immunomodulatory effects. Numbers are amino acids of the human protein.

Figure 2

Glucocorticoid receptor co-regulators. The Glucocorticoid Receptor (GR) binds to Glucocorticoid Receptor Binding Sites (GBS) in open chromatin. GR interacts with other transcription factors (TFs) and recruits co-activators or co-repressors, such as: the Steroid Receptor co-activators 1, 2, and 3 (SRC-1, SRC-2, and SRC-3); the histone acetyl transferases CREB binding protein (CBP) and p300; the Nuclear Receptor co-repressors NCOR1 and NCOR2 (NCOR, SMRT), which recruit histone deacetylases 1 and 3 (HDACs); and the SWItch/Sucrose-Non Fermentable (SWI/SNF) chromatin remodeling complex.

Figure 3

Models for inflammatory gene regulation by the glucocorticoid receptor. Upon ligand binding (GCs), the glucocorticoid receptor (GR) is released from heat shock proteins (Hsp) and translocates to the nucleus. Inflammation can be activated by lipopolysaccharide (LPS) binding to Toll-like receptor 4 (TLR4). TLR4 signaling results in the activation of NF-κB, AP-1, and other inflammatory transcription factors that bind and regulate pro-inflammatory target genes. Different mechanisms have been proposed for GR's potent anti-inflammatory actions, i.e., binding to Glucocorticoid Response Elements (GREs), to composite GREs together with other transcription factors, to negative GREs (nGRE), by tethering to DNA-bound transcription factors, by competing with other factors for DNA binding sites or by non-genomic actions.

Figure 4

Glucocorticoid receptor mutant mouse models of inflammation. Overview of the mouse lines discussed in this article. (A) GR^dim mice are more sensitive during LPS-, CLP-, or TNF inflammation. GR^dim mice are refractory to GC treatment in models of skin inflammation, acute lung injury and arthritis. (B) In GR^LckCre mice, GR is lacking in T-cells, making them refractory to GC treatment during arthritis. (C) GR^{Col1a2CreERT2} (lacking GR in fibroblasts) show delayed GC-induced suppression in arthritis. (D) GR K310R mutant mice lack GR SUMOylation and show impaired control of skin inflammation. (E) GR-C3 mice, lacking the most active GR isoform C3, are more sensitive to LPS-induced endotoxic shock. (F) During fracture, GR is necessary in all cells, as shown by GR^{gtRosaCreERT2} (tamoxifen-induced ubiquitous Cre-mediated recombination) for fracture healing. (G) GR^LysMCre mice (GR is deleted in myeloid cells) show no proper healing in LPS-or CLP-sepsis, skin inflammation, acute lung injury, DSS colitis, cardiac healing, and Parkinson disease. The skin, lungs, bones, intestine, heart and brain cartoons were obtained from Servier Medical Art.