Abstract
Endogenous retinoids like all-trans retinoic acid (ATRA) play important roles in skin homeostasis and skin-based immune responses. Moreover, retinoid signaling was found to be dysregulated in various skin diseases. The present study used topical application of selective agonists and antagonists for retinoic acid receptors (RARs) α and γ and retinoid-X receptors (RXRs) for two weeks on mouse skin in order to determine the role of retinoid receptor subtypes in the gene regulation in skin. We observed pronounced epidermal hyperproliferation upon application of ATRA and synthetic agonists for RARγ and RXR. ATRA and the RARγ agonist further increased retinoid target gene expression (Rbp1, Crabp2, Krt4, Cyp26a1, Cyp26b1) and the chemokines Ccl17 and Ccl22. In contrast, a RARα agonist strongly decreased the expression of ATRA-synthesis enzymes, of retinoid target genes, markers of skin homeostasis, and various cytokines in the skin, thereby markedly resembling the expression profile induced by RXR and RAR antagonists. Our results indicate that RARα and RARγ subtypes possess different roles in the skin and may be of relevance for the auto-regulation of endogenous retinoid signaling in skin. We suggest that dysregulated retinoid signaling in the skin mediated by RXR, RARα and/or RARγ may promote skin-based inflammation and dysregulation of skin barrier properties.
Highlights
The nuclear hormone receptors retinoic acid receptors (RAR) a, b, and c and retinoid X receptors (RXR) a, b, and c are liganddependent transcription factors that can be activated by retinoids
RAR-RXR heterodimers regulate the expression of multiple genes in skin and various other tissues [1], while their transcriptional activity is dependent on the RAR-activating ligand [2,3,4]
The main finding of this study was the strong difference between the positive retinoid-mediated signaling via RARc pathways in contrast to the negative retinoid-mediated signaling via RARa in the skin
Summary
The nuclear hormone receptors retinoic acid receptors (RAR) a, b, and c and retinoid X receptors (RXR) a, b, and c are liganddependent transcription factors that can be activated by retinoids. RAR-RXR heterodimers regulate the expression of multiple genes in skin and various other tissues [1], while their transcriptional activity is dependent on the RAR-activating ligand [2,3,4]. RAR and RXR subtypes differ in ligand specificity and/or affinity [9,11,12,13,14], it can be assumed that their contribution to gene expression patterns in skin differs, depending on quantitative receptor distribution, on the nature and level of coregulators, as well as on available retinoid receptor-selective agonists and antagonists. Retinoid metabolism and concentrations in skin are tightly regulated ensuring sufficient levels of the endogenous pan-RAR activator all-trans retinoic acid (ATRA) [2,21,22]. Altered retinoidmediated signaling in skin of these patients may be a result of activation or antagonism of specific retinoid receptor subtypes under disease conditions
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