Natalia M. Fossas De Mello
Wendy B. Bollag
Ameena Ali
Yonghong Luo
Vivek Choudhary
Husam Bensreti
Joseph Shaver
Meghan McGee-Lawrence

Universidad Central del Caribe, Bayamón, Puerto Rico
Departments of Physiology and Cellular Biology and Anatomy, Augusta University, Augusta, Georgia, United States

Introduction

The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) regulate skin homeostasis, inflammation, and repair. Dysregulation of their signaling contributes to inflammatory skin disorders such as psoriasis and atopic dermatitis. While endogenous glucocorticoids help maintain skin homeostasis, prolonged pharmacological use can lead to adverse effects, including epidermal atrophy and delayed wound healing.

Methods

To investigate MR/GR interactions in skin physiology, 20-month-old female C57BL/6 mice were treated for eight weeks with selective GR and MR antagonists, Recorilant (GR antagonist), Miricorilant (GR/MR antagonist), and Eplerenone (MR antagonist), before skin harvest for epidermal thickness and gene expression analysis. Since aging is associated with increased glucocorticoid levels, older mice provide a relevant model for studying MR/GR signaling in skin.

Results

Miricorilant increased expression of three keratinocyte differentiation markers and decreased two inflammatory markers. It also upregulated an MR/GR target gene while reducing a dermal extracellular matrix (ECM) component. Proliferative keratinocyte markers, regulators of MR/GR activity, and epidermal thickness showed no significant changes across treatments.

Conclusions

While receptor antagonism was expected to exhibit similar effects to receptor knockouts, our findings suggest a more complex regulatory interaction. This discrepancy may be due to MR and GR functioning as transcription factors, releasing chaperones and recruiting coactivators to regulate gene expression. Knockout may allow free chaperones or coactivators to modulate other nuclear receptors, potentially altering gene expression. In contrast, antagonists block receptor activation while preserving receptor interactions with other signaling components, which may alter receptor dynamics. Given that MR and GR antagonists are in, or under investigation for, clinical use, understanding their systemic effects, including potential skin-related consequences, is crucial. Additionally, MR antagonism may help counteract glucocorticoid-induced epidermal atrophy. These findings highlight the intricate interaction between MR and GR in skin homeostasis and may provide new avenues for treating inflammatory cutaneous diseases and effects of aging on skin.

Keywords

Mineralocorticoid receptor, Glucocorticoid receptor, Skin homeostasis, Inflammation, Keratinocyte differentiation

IACUC Approval Number

2014-0673

Acknowledgments

This research was supported in part by grant awards from the National Institute on Aging (#P01AG036675 to MM-L and #T35AG067577 to WBB). WBB was supported by a Veterans Affairs Research Career Scientist Award #IK6 BX005691.