title: 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.
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Boix
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sevilla
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: Zara
authors.initials: Z
authors.lastname: Sáez
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Carceller
authors.affiliation: Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain. Electronic address: pperez@ibv.csic.es.
authors.forename: Paloma
authors.initials: P
authors.lastname: Pérez
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011897:Random Allocation; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*; D014947:Wounds and Injuries / Q000378:metabolism* / Q000473:pathology
chemical_list: D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid