091 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 (GR) and the mineralocorticoid receptor (MR), transcription factors that recognize identical hormone responsive elements (HREs).Whether epidermal MR mediates beneficial or deleterious GC effects is of great interest for improving GC-based skin therapies. MR epidermal knock-out (MR EKO ) 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 EKO mice showed increased susceptibility to PMA-induced inflammation with higher cytokine induction.Likewise, cultured MR EKO keratinocytes had increased PMA-induced NF-B activation, highlighting an anti-inflammatory function for MR. GC-induced transcription was reduced in MR EKO keratinocytes, at least partially due to decreased recruitment of GR to HRE-containing sequences. Our results support a role for epidermal MR in adult skin homeostasis and demonstrate non-redundant roles for MR and GR in mediating GC actions.3