Glucocorticoid-dependent transcription in skin requires epidermal expression of the glucocorticoid receptor and is modulated by the mineralocorticoid receptor

Abstract

Glucocorticoid (GC) actions are mediated through two closely related ligand-dependent transcription factors, the GC receptor (GR) and the mineralocorticoid receptor (MR). Given the wide and effective use of GCs to combat skin inflammatory diseases, it is important to understand the relative contribution of these receptors to the transcriptional response to topical GCs. We evaluated the gene expression profiles in the skin of mice with epidermal-specific loss of GR (GR ^EKO), MR (MR ^EKO), or both (double KO; DKO) in response to dexamethasone (Dex). The overall transcriptional response was abolished in GR ^EKO and DKO skin suggesting dependence of the underlying dermis on the presence of epidermal GR. Indeed, the observed dermal GC resistance correlated with a constitutive decrease in GR activity and up-regulation of p38 activity in this skin compartment. Upon Dex treatment, more than 90% of differentially expressed genes (DEGs) in CO overlapped with MR ^EKO. However, the number of DEGs was fourfold increased and the magnitude of response was higher in MR ^EKO vs CO, affecting both gene induction and repression. Taken together our data reveal that, in the cutaneous transcriptional response to GCs mediated through endogenous receptors, epidermal GR is mandatory while epidermal MR acts as a chief modulator of gene expression.