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11 págs., 6 figuras. All data generated or analyzed during this study are included in this published article (and its SupplementaryInformation fles) at https://doi.org/10.1038/s41598-020-75853-5., 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., Tis work was supported by grant SAF2017-88046-R (MICINN, Spanish Government). J. Bigas is recipient of FPI fellowship of MINECO. We thank NURCAMEIN (SAF2017-90604-REDT) for support for dissemination.We also thank Julia Boix for assisting with the animal experiments.

10 páginas, 5 figuras. Supplementary material is linked to the online version of the paper at https://doi.org/10.1016/j.jid.2020.03.933, The increased production of endogenous glucocorticoids (GCs) in the skin of the elderly population contributes to age-related defects strikingly similar to those occurring after pharmacologic treatments with GCs. GCs act through the ligand-dependent transcription factors GC receptor (GR) and mineralocorticoid receptor (MR). We reported that epidermal MR plays nonredundant roles relative to GR in adult mouse skin homeostasis; however, its relative contribution to natural skin aging has not been previously investigated. A 13-month-old MR epidermal knockout (MREKO) mice showed differential features of aging relative to controls (CO) in all skin compartments. MREKO mice were resistant to age-induced epidermal atrophy but showed reduced dermal thickness, with decreased collagen deposition and decreased SMAD2 and 3 activity. Importantly, the dermal white adipose tissue (dWAT) was 2.5-fold enlarged in 13-month MREKO versus CO, featuring adipocyte hyperplasia and hypertrophy at least in part through early increases in Pparg. These changes correlated with compartment-specific alterations in GC signaling. In addition, conditioned medium from MREKO keratinocytes increased adipocyte differentiation, indicating paracrine regulation of adipogenesis through mechanisms that include activation of β-catenin signaling. These findings highlight the importance of epidermal MR in regulating cross-talk among skin compartments in naturally aged skin through GC and β-catenin signaling pathways., This research was supported by grant SAF2017-880464-R (Ministerio de Economı´a y Competitividad [MINECO], Spanish Government). JB is a recipient of Formacio´n Personal Investigador fellowship from MINECO (BES2015- 072722). The authors thank MINECO Nuclear Receptors in Cancer, Metabolism, and Inflammation for Networks of Excellence grant (SAF2017-90604-REDT).

14 páginas, 6 figuras. Material suplementario en https://doi.org/10.1038/s41419-018-0673-z., 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., This work was supported by grants SAF2014-59474-R and SAF2017-88046-R (MINECO, Spanish Government). J.B. is recipient of FPI fellowship from MINECO (BES2015-072722). We thank COST ADMIRE BM-1301 and NURCAMEIN (SAF2015-71878-REDT and SAF2017-90604-REDT) for support for dissemination.

10 páginas, 4 figuras, 1 tabla., Primary aldosteronism (PA) is a disease characterized by high aldosterone levels caused by benign adrenal tumors being the most frequent cause of secondary hypertension. Aldosterone plays vital physiological roles through the mineralocorticoid receptor (MR) but in certain cell types, it can also activate the glucocorticoid (GC) receptor (GR). Both MR and GR are structurally and functionally related and belong to the same family of ligand-dependent transcription factors that recognize identical GC regulatory elements (GREs) on their target genes. GCs play key roles in skin pathophysiology acting through both GR and MR; however, the effects of aldosterone and the potential association of PA and skin disease were not previously addressed. Skin samples from PA revealed histopathological alterations relative to control subjects, featuring epidermal hyperplasia, impaired differentiation, and increased dermal infiltrates, correlating with increased NF-κB signaling and up-regulation of TNF-A and IL-6 cytokines. PA skin samples also showed significantly higher expression of MR, GR, and HSD11B2. In cultured keratinocytes, aldosterone treatment increased GRE transcriptional activity which was significantly inhibited by co-treatment with GR- and MR-antagonists. This study demonstrates that high levels of aldosterone in PA patients correlate with skin anomalies and inflammatory features associated with abnormal GR/MR activation in epidermal keratinocytes., This work was supported by grant SAF2014-59474-R (MINECO, Spanish Government). J. Boix and J. Bigas are recipients of FPI fellowships of MINECO. We thank COST ADMIRE BM-1301 and NURCAMEIN (SAF2015-71878-REDT) for support for dissemination. We thank Jose Nieto for assistance with histopathological work. We are indebted to the patients and healthcare professionals that collaborated in this study.