091 Epidermal mineralocorticoid receptor plays beneficial and adverse effects in skin and mediates glucocorticoid responses

Abstract

Endogenous and synthetic glucocorticoids (GCs) are important in regulating skin homeostasis and also in combating cutaneous inflammatory diseases. However, chronic GC treatments cause some adverse effects that limit their therapeutic use. GCs bind and activate the GC receptor (GR) and the mineralocorticoid receptor (MR), both nuclear receptors act as ligand-dependent transcription factors that recognize the same hormone responsive elements (HREs) in their target genes. While the function of GR in skin pathophysiology has been widely studied, the role of MR in this tissue needs further analysis. Moreover, whether it mediates beneficial or deleterious GC effects is of great interest for improving GC-based skin therapies. In order to understand the role of MR in the skin we have generated MR epidermal knock-out (MREKO) mice and analyzed their response to sodium dedocyl sulfate (SDS), phorbol 12-myristate 13-acetate (PMA), wound healing and long-term GCs treatments. We also generated and characterized keratinocyte cell lines from CO and MREKO dorsal skin and performed complementary in vitro assays. MREKO 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 skin barrier disruption and inflammatory stimuli and decreased their capacity of wounding. Likewise, cultured MREKO keratinocytes had increased PMA-induced NF-kB activation, highlighting an anti-inflammatory function for MR. GC-induced transcription was reduced in MREKO keratinocytes at least partly due to reduced GR recruitment to HRE-containing target genes. Our results support a role for epidermal MR in adult skin pathophysiology and demonstrate non-redundancy with GR. These data must be taken into account for the design of GC-based skin therapies.