Mineralocorticoid receptor blockade improves glucocorticoid‐induced skin atrophy but partially ameliorates anti‐inflammatory actions in an irritative model in human skin explants

Boix, Julia; Nguyen, Van Tuan; Farman, Nicolette; Aractingi, S.; Pérez, Paloma

doi:10.1111/exd.13473

Cited by 15 publications

(21 citation statements)

References 13 publications

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“…There has also been interest in developing topical formulations of SP (Kelidari et al, 2015) to limit the systemic and potentially endocrine-disrupting effects of orally administered SP. Moreover, the topical use of SP and related mineralocorticoid receptor antagonists have been shown in clinical trials to counteract epidermal atrophy and the inhibition of wound healing caused by glucocorticoid treatment (Boix et al, 2018;Maubec et al, 2015;Nguyen et al, 2016). Chronic treatment with topical SP formulations, especially as proposed for use in damaged skin, would likely result in higher levels of SP than those associated with systemic treatment.…”

Section: Discussionmentioning

confidence: 99%

Spironolactone Depletes the XPB Protein and Inhibits DNA Damage Responses in UVB-Irradiated Human Skin

Kemp

Krishnamurthy

Kent

et al. 2019

Journal of Investigative Dermatology

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UVB wavelengths of light induce the formation of photoproducts in genomic DNA that are potentially mutagenic and detrimental to epidermal cell function. The mineralocorticoid and androgen receptor antagonist spironolactone (SP) was recently identified as an inhibitor of UV photoproduct removal in human cancer cells in vitro via its ability to promote the rapid proteolytic degradation of the DNA repair protein XPB. Using normal human keratinocytes in vitro and skin explants ex vivo, we found that SP rapidly depleted XPB protein in both systems and abrogated two major responses to UVB-induced DNA damage, including the removal of UV photoproducts from genomic DNA and the activation of ATR/ATM DNA damage kinase signaling. These effects were also correlated with both mutagenesis and a predisposition to UVB-induced cell death but were unique to SP, because neither the SP metabolites canrenone and 7α-thiomethylspironolactone nor the more specific mineralocorticoid receptor antagonist eplerenone affected XPB protein levels or the UVB response. Our findings provide an approach for studying XPB and its roles in the UVB DNA damage response in human skin ex vivo and indicate that SP may increase UVB mutagenesis and skin cancer risk in certain individuals.

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Section: Discussionmentioning

confidence: 99%

Spironolactone Depletes the XPB Protein and Inhibits DNA Damage Responses in UVB-Irradiated Human Skin

Kemp

Krishnamurthy

Kent

et al. 2019

Journal of Investigative Dermatology

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“…By using genetic and pharmacological approaches in mice and human skin explants, we and others demonstrated that blockade of the MR effectively improved GC-induced skin atrophy 5 , 16 , 18 . However, caution is advised for treating inflamed skin with GCs and MR inhibitors as their combined use decreased the anti-inflammatory actions of GCs in SDS-treated human skin explants 33 .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…These findings opened the attractive possibility of using combined therapy with GCs and pharmacological MR antagonists to improve GC-induced skin atrophy. However, in a model of contact dermatitis with human skin explants, MR blockade reduced GC-induced skin atrophy, but limited the repression of some inflammatory cytokines, suggesting that MR may be required for the full therapeutic response to GCs in this tissue [ 99 ]. This possibility is supported by the observations from our laboratory that mice lacking epidermal MR, similar to those lacking GR in this tissue, are more susceptible to skin inflammation [ 13 , 14 ].…”

Section: Gr and Mr In Adult Skin Homeostasismentioning

confidence: 99%

Roles of the Glucocorticoid and Mineralocorticoid Receptors in Skin Pathophysiology

Sevilla

Pérez

2018

IJMS

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The nuclear hormone receptor (NR) superfamily comprises approximately 50 evolutionarily conserved proteins that play major roles in gene regulation by prototypically acting as ligand-dependent transcription factors. Besides their central role in physiology, NRs have been largely used as therapeutic drug targets in many chronic inflammatory conditions and derivatives of their specific ligands, alone or in combination, are frequently prescribed for the treatment of skin diseases. In particular, glucocorticoids (GCs) are the most commonly used compounds for treating prevalent skin diseases such as psoriasis due to their anti-proliferative and anti-inflammatory actions. However, and despite their therapeutic efficacy, the long-term use of GCs is limited because of the cutaneous adverse effects including atrophy, delayed wound healing, and increased susceptibility to stress and infections. The GC receptor (GR/NR3C1) and the mineralocorticoid receptor (MR/NR3C2) are members of the NR subclass NR3C that are highly related, both structurally and functionally. While the GR is ubiquitously expressed and is almost exclusively activated by GCs; an MR has a more restricted tissue expression pattern and can bind GCs and the mineralocorticoid aldosterone with similar high affinity. As these receptors share 95% identity in their DNA binding domains; both can recognize the same hormone response elements; theoretically resulting in transcriptional regulation of the same target genes. However, a major mechanism for specific activation of GRs and/or MRs is at the pre-receptor level by modulating the local availability of active GCs. Furthermore, the selective interactions of each receptor with spatio-temporally regulated transcription factors and co-regulators are crucial for the final transcriptional outcome. While there are abundant genome wide studies identifying GR transcriptional targets in a variety of tissue and cell types; including keratinocytes; the data for MR is more limited thus far. Our group and others have studied the role of GRs and MRs in skin development and disease by generating and characterizing mouse and cellular models with gain- and loss-of-function for each receptor. Both NRs are required for skin barrier competence during mouse development and also play a role in adult skin homeostasis. Moreover, the combined loss of epidermal GRs and MRs caused a more severe skin phenotype relative to single knock-outs (KOs) in developing skin and in acute inflammation and psoriasis, indicating that these corticosteroid receptors play cooperative roles. Understanding GR- and MR-mediated signaling in skin should contribute to deciphering their tissue-specific relative roles and ultimately help to improve GC-based therapies.

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Mineralocorticoid receptor blockade improves glucocorticoid‐induced skin atrophy but partially ameliorates anti‐inflammatory actions in an irritative model in human skin explants

Cited by 15 publications

References 13 publications

Spironolactone Depletes the XPB Protein and Inhibits DNA Damage Responses in UVB-Irradiated Human Skin

Spironolactone Depletes the XPB Protein and Inhibits DNA Damage Responses in UVB-Irradiated Human Skin

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

Roles of the Glucocorticoid and Mineralocorticoid Receptors in Skin Pathophysiology

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