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

Abstract

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 (MR EKO ) mice showed differential features of aging relative to controls (CO) in all skin compartments. MR EKO 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 MR EKO 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 MR EKO keratinocytes increased adipocyte differentiation, indicating paracrine regulation of adipogenesis through mechanisms that include activation of b-catenin signaling. These findings highlight the importance of epidermal MR in regulating cross-talk among skin compartments in naturally aged skin through GC and bcatenin signaling pathways.

The mineralocorticoid receptor in skin disease

“…Also, keratinocyte‐specific alterations in MR EKO may shift the homeostasis of other skin compartments, leading to differential glucocorticoid responses in the whole tissue (Figure 3). These data are in line with the fact that epidermal MR loss has paracrine actions on dermal adipocytes in middle‐aged MR EKO mice (Bigas et al, 2020).…”

“…In this model, MR up‐regulation correlated with ageing‐related adverse changes in the skin, which were suppressed by topical application of spironolactone (Nagase et al, 2013). Recent work also demonstrated that epidermal MR is involved in physiological skin ageing due to enhanced levels of endogenous skin glucocorticoids (Bigas et al, 2020). Although middle‐aged control mice featured partial atrophy in all skin compartments, histopathological and molecular changes in MR EKO mice were compartment specific (Figure 3).…”

“…MR EKO mice were resistant to age‐induced epidermal atrophy but showed reduced dermal thickness, collagen deposition and SMAD2/3 activity relative to controls. However, the dermal white adipose tissue (dWAT) in the hypodermis was significantly enlarged in 13‐month MR EKO mice, featuring increased adipocyte size and number (Bigas et al, 2020). The unique impact of epidermal MR loss on the dermal adipose depot in these mice supports a role of the epidermis in regulating adipogenesis through yet unidentified paracrine mediators.…”

The myeloid mineralocorticoid receptor regulates dermal angiogenesis and inflammation in glucocorticoid‐induced impaired wound healing

“…Also, an increase in MR expression in keratinocytes induces atrophy of the mouse epidermis (Sainte Marie et al, 2007 ), whereas mice in which the MR was inactivated in epithelial cells showed increased keratinocyte proliferation and differentiation (Boix et al, 2016 ). Deletion of the MR in keratinocytes was shown to alter the homeostasis of all skin layers in aged mice, with reduced dermal thickness and decreased collagen deposition (Bigas et al, 2020 ). We previously showed that topical MR blockade accelerates skin wound healing in diabetic mice (Nguyen et al, 2020 ).…”