Epidermal glucocorticoid and mineralocorticoid receptors act cooperatively to regulate epidermal development and counteract skin inflammation

Abstract

Endogenous and synthetic glucocorticoids (GCs) regulate epidermal development and combat skin inflammatory diseases. GC actions can be mediated through the GC receptor (GR) and/or the mineralocorticoid receptor (MR), highly homologous ligand-activated transcription factors. While the role of GR as a potent anti-inflammatory mediator is well known, that of MR is not as clear, nor is whether these receptors cooperate or antagonize each other in the epidermis. To address this, we generated mice with epidermal-specific loss of both receptors (double knockout, DKO), and analyzed the phenotypical and functional consequences relative to single KOs or controls (CO). At birth, DKO epidermis displayed a phenotype of defective differentiation and inflammation, which was more severe than in either single KO, featuring neutrophil-containing infiltrates, and gene dysregulation characteristic of human psoriatic lesions. This phenotype resolved spontaneously. However, in adulthood, single or combined loss of GC receptors increased susceptibility to inflammation and hyperproliferation triggered by phorbol ester which, different to CO, was not effectively counteracted by GC treatment. Also, DKOs were more susceptible to imiquimod-induced psoriasis than CO showing severe defective epidermal differentiation and microabcesses while single KOs showed an intermediate response. Immortalized DKO keratinocytes featured increased proliferation kinetics and reduced cell size, a unique phenotype relative to single KO cells. The lack of GR and MR in keratinocytes, individual or combined, caused constitutive increases in p38 and ERK activities, which were partially reversed upon reinsertion of receptors into DKO cells. DKO keratinocytes also displayed significant increases in AP-1 and NF-κB transcriptional activities, which were partially rescued by ERK and p38 inhibition, respectively. Reinsertion of GR and MR in DKO keratinocytes resulted in physical and cooperative functional interactions that restored the transcriptional response to GCs. In conclusion, our data have revealed that epidermal GR and MR act cooperatively to regulate epidermal development and counteract skin inflammation.

Epidermal Mineralocorticoid Receptor Inactivation Affects the Homeostasis of All Skin Layers in Chronologically Aged Mice

“…In MR EKO dermis, Nr3c2 levels increased by two-fold, and there was a trend toward increased GR activity (Figure 2a and b; two-fold, P ¼ 0.054). These changes were concomitant with the upregulation of Ddit4, Fkbp51, and Hsd11b1 in this compartment (2-fold, 7-fold, and 2.8-fold, respectively; Figure 2c), suggesting cooperative transcriptional effects of GR and MR (Bigas et al, 2018;Boix et al, 2016). The increased levels of Ddit4 and Fkbp51 are consistent with their reported role as skin atrophogenes, as the MR EKO dermis showed atrophy (Baida et al, 2018(Baida et al, , 2015 (Figure 1a and d).…”

Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade

“…Boix et al(2016) demonstrated that epidermal deletion of MRs leads to increased keratinocyte proliferation and differentiation . Other studies proposed that epidermal MR cooperates with GC receptors, acting as an anti-inflammatory factor to counteract skin inflammation and regulate epidermal development in inflamed skin (Bigas et al, 2018;Sevilla and Pérez, 2018).…”

Roles of the Glucocorticoid and Mineralocorticoid Receptors in Skin Pathophysiology

“…These experiments demonstrate that the interaction of both receptors at the same target promoter, which occurs with different kinetics, results in specific and distinct transcriptional signatures and highlights the complexity of gene regulation by GR and MR [ 49 ]. In keratinocytes, GRs and MRs can heterodimerize in response to Dex and synergistically activate a GRE-luciferase reporter [ 50 ], however the relative binding of homo- and hetero-dimers to target genes in this cell type is unknown. An area of future interest is the identification of MBS in keratinocytes, as comparison of genomic bound regions in ChIP-seq experiments carried out in different cell types is limited by the well-known context and cell-type specific actions of these TFs.…”

“…HSD11B1 is expressed in human and mouse epidermis and dermis, and is upregulated in differentiating keratinocytes [ 60 , 61 ]. HSD11B2 is also present in human and mouse suprabasal epidermis as well as in sweat glands, an important target for aldosterone-MR regulation [ 10 , 50 , 62 , 63 , 64 ]. However, there is no evidence of local aldosterone synthesis in the epidermal or dermal cells of the skin [ 57 ].…”