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 (GREKO), MR (MREKO), or both (double KO; DKO) in response to dexamethasone (Dex). The overall transcriptional response was abolished in GREKO 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 MREKO. However, the number of DEGs was fourfold increased and the magnitude of response was higher in MREKO 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.
Highlights
Glucocorticoid (GC) actions are mediated through two closely related ligand-dependent transcription factors, the GC receptor (GR) and the mineralocorticoid receptor (MR)
This study addresses for the first time the relative contribution of endogenous GR and MR to the transcriptional response to topically applied GCs
Our data showed that the epidermal loss of GR or MR resulted in opposite responses to GCs: while G REKO mice were refractory to Dex, M REKO featured both a higher number of Dexregulated genes and an increased magnitude of response (Figs. 1, 3, and 6)
Summary
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 (GREKO), MR (MREKO), or both (double KO; DKO) in response to dexamethasone (Dex). We previously assessed the relative roles of these receptors in the skin by generating mice with epidermal-specific inactivation of GR, MR, or both (hereafter, GR epidermal KO/GREKO, MR epidermal KO/MREKO, or double GR/MR epidermal KO/DKO, respectively)[6,7,8] The characterization of these mouse models demonstrated that: i) during development, epidermal GR and MR play non-overlapping functions and act cooperatively to regulate skin morphogenesis; and ii) in adulthood, neither. This study aims to understand the global contribution of the endogenous GC receptors, individual or combined, to the GC transcriptional response in the whole tissue, by using an in vivo approach
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