Epidermal Mineralocorticoid Receptor Plays Beneficial and Adverse Effects in Skin and Mediates Glucocorticoid Responses

Abstract

Glucocorticoids (GCs) regulate skin homeostasis and combat cutaneous inflammatory diseases; however, adverse effects of chronic GC treatments limit their therapeutic use. GCs bind and activate the GC receptor and the mineralocorticoid receptor (MR), transcription factors that recognize identical hormone responsive elements. Whether epidermal MR mediates beneficial or deleterious GC effects is of great interest for improving GC-based skin therapies. MR epidermal knockout mice exhibited increased keratinocyte proliferation and differentiation and showed resistance to GC-induced epidermal thinning. However, crucially, loss of epidermal MR rendered mice more sensitive to inflammatory stimuli and skin damage. MR epidermal knockout mice showed increased susceptibility to phorbol 12-myristate 13-acetate-induced inflammation with higher cytokine induction. Likewise, cultured MR epidermal knockout keratinocytes had increased phorbol 12-myristate 13-acetate-induced NF-κB activation, highlighting an anti-inflammatory function for MR. GC-induced transcription was reduced in MR epidermal knockout keratinocytes, at least partially due to decreased recruitment of GC receptor to hormone responsive element-containing sequences. Our results support a role for epidermal MR in adult skin homeostasis and demonstrate nonredundant roles for MR and GC receptor in mediating GC actions.

Endogenous Glucocorticoid Deficiency in Psoriasis Promotes Inflammation and Abnormal Differentiation

“…(Figure 3d). Of note, as mineralcorticoid receptor has been implicated in glucocorticoid responses in skin (Boix et al , 2016), mRNA expression of the mineralcorticoid receptor was also decreased in PP compared to PN and NN skin (2.2-fold decreased, p<0.01).…”

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

“…Glucocorticoids bind and activate two closely related receptors, the GC receptor (GR) and the mineralocorticoid receptor (MR). Our recent work using genetic and pharmacological approaches in mouse skin and healthy skin of volunteers and human skin explants has shown that MR inactivation ameliorates GC‐induced skin atrophy . In both settings, MR blockade improved the epidermal thinning partially reversing the keratinocyte proliferation inhibition induced by topical GC treatments .…”

Defective glucocorticoid receptor signaling and keratinocyte-autonomous defects contribute to skin phenotype of mouse embryos lacking the Hsp90 co-chaperone p23

“…One complication is that Dex also activates the mineralocorticoid receptor (MR) albeit with reduced affinity and efficiency [45]. MR in the epidermis does play an important role, mediates some glucocorticoid effects and is required along with GR for proper keratinocyte differentiation [46]. While MR, just like GR, is itself an Hsp90 client [47], its p23 dependence is less well understood.…”