ANIMAL MODELS OF SKIN DISEASES
Our research group is interested in understanding the mechanisms that regulate the physiopathology of the skin, the largest organ of the body, required for survival in mammals due to its barrier function that confers protection from dehydration, external damage, and pathogens. The skin is often affected by chronic inflammatory conditions such as psoriasis and atopic dermatitis, which show co-morbidity with metabolic diseases. The skin is comprised of functionally differentiated layers, the epidermis, dermis, and hypodermis, which have extensive functional crosstalk among them. Importantly, as a neuro–endocrine–immune organ able to secrete neuropeptides, hormones, and cytokines, the skin can also modulate whole-body homeostasis.
Endogenous glucocorticoid (GC) hormones are major regulators of skin homeostasis, and synthetic GCs are commonly and effectively used for treating skin diseases due to their anti-inflammatory actions. However, due to pleiotropic actions, excess GCs -endogenous or pharmacological- result in adverse outcome in metabolism and immunity, impairing quality of life. In skin, chronic GC therapies can cause atrophy, increased fragility and bruising, impaired wound healing, and increased infection risk.
GCs act through a dual system formed by two highly related intracellular proteins, the GC receptor (GR/NR3C1) and the mineralocorticoid receptor (MR/NR3C2), which act as ligand-dependent transcription factors. Our group has contributed to dissect the relative roles of these receptors in skin physiopathology by generating and characterizing mouse and cellular models with epidermal-specific gain- and loss-of-function of GR, MR, or both. Our data demonstrate that these proteins are pivotal for the development, aging, and homeostasis of this tissue via non-overlapping functions.
Recently, we showed that genetic and pharmacological inactivation of MR in mouse and human skin was partially able to reverse skin atrophy upon GC treatments, supporting the combined use of MR antagonists and GR ligands for the treatment of inflammatory skin disorders. Also, we demonstrated that GC transcriptional outcome in skin is crucially mediated by GR while MR modulates the specificity and magnitude of the response. Currently we address the patterns and kinetics of GR/MR genomic binding in keratinocytes, as well as the selective GR/MR interactions with cell type-specific transcription factors and co-regulators. These studies should ultimately help to improve GC-based therapies for treating cutaneous diseases.