Roles of the Glucocorticoid and Mineralocorticoid Receptors in Skin Pathophysiology

Abstract

The nuclear hormone receptor (NR) superfamily comprises approximately 50 evolutionarily conserved proteins that play major roles in gene regulation by prototypically acting as ligand-dependent transcription factors. Besides their central role in physiology, NRs have been largely used as therapeutic drug targets in many chronic inflammatory conditions and derivatives of their specific ligands, alone or in combination, are frequently prescribed for the treatment of skin diseases. In particular, glucocorticoids (GCs) are the most commonly used compounds for treating prevalent skin diseases such as psoriasis due to their anti-proliferative and anti-inflammatory actions. However, and despite their therapeutic efficacy, the long-term use of GCs is limited because of the cutaneous adverse effects including atrophy, delayed wound healing, and increased susceptibility to stress and infections. The GC receptor (GR/<i>NR3C1</i>) and the mineralocorticoid receptor (MR/<i>NR3C2</i>) are members of the NR subclass NR3C that are highly related, both structurally and functionally. While the GR is ubiquitously expressed and is almost exclusively activated by GCs; an MR has a more restricted tissue expression pattern and can bind GCs and the mineralocorticoid aldosterone with similar high affinity. As these receptors share 95% identity in their DNA binding domains; both can recognize the same hormone response elements; theoretically resulting in transcriptional regulation of the same target genes. However, a major mechanism for specific activation of GRs and/or MRs is at the pre-receptor level by modulating the local availability of active GCs. Furthermore, the selective interactions of each receptor with spatio-temporally regulated transcription factors and co-regulators are crucial for the final transcriptional outcome. While there are abundant genome wide studies identifying GR transcriptional targets in a variety of tissue and cell types; including keratinocytes; the data for MR is more limited thus far. Our group and others have studied the role of GRs and MRs in skin development and disease by generating and characterizing mouse and cellular models with gain- and loss-of-function for each receptor. Both NRs are required for skin barrier competence during mouse development and also play a role in adult skin homeostasis. Moreover, the combined loss of epidermal GRs and MRs caused a more severe skin phenotype relative to single knock-outs (KOs) in developing skin and in acute inflammation and psoriasis, indicating that these corticosteroid receptors play cooperative roles. Understanding GR- and MR-mediated signaling in skin should contribute to deciphering their tissue-specific relative roles and ultimately help to improve GC-based therapies.