Nuclear receptor function in skin health and disease: therapeutic opportunities in the orphan and adopted receptor classes

Abstract

The skin forms a vital barrier between an organism's external environment, providing protection from pathogens and numerous physical and chemical threats. Moreover, the intact barrier is essential to prevent water and electrolyte loss without which terrestrial life could not be maintained. Accordingly, acute disruption of the skin through physical or chemical trauma needs to be repaired timely and efficiently as sustained skin pathologies ranging from mild irritations and inflammation through to malignancy impact considerably on morbidity and mortality. The Nuclear Hormone Receptor Family of transcriptional regulators has proven to be highly valuable targets for addressing a range of pathologies, including metabolic syndrome and cancer. Indeed members of the classic endocrine sub-group, such as the glucocorticoid, retinoid, and Vitamin D receptors, represent mainstay treatment strategies for numerous inflammatory skin disorders, though side effects from prolonged use are common. Emerging evidence has now highlighted important functional roles for nuclear receptors belonging to the adopted and orphan subgroups in skin physiology and patho-physiology. This review will focus on these subgroups and explore the current evidence that suggests these nuclear receptor hold great promise as future stand-alone or complementary drug targets in treating common skin diseases and maintaining skin homeostasis.

Keywords: LXR; NR4A; Nuclear receptor; Orphan receptors; PPAR; Wound healing.

Fig. 1

Skin is comprised of the outer epidermis, the dermis, and the hypodermis. The epidermis is made up of four distinct layers, such as stratum basale (SB), stratum spinosum (SS), stratum granulosum (SG), and the stratum corneum (SC), representing keratinocytes at different stages of differentiation. Members of the adopted and orphan nuclear receptors are involved in critical processes, such as wound repair, permeability barrier homeostasis, and repair of UV damage. A number of receptors may be targeted to address skin inflammation that underpins a number of acute and chronic skin disorders