Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.
PLoS One. 2013 Apr 24;8(4):e62643. doi: 10.1371/journal.pone.0062643. Print 2013.
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.
内源性视黄酸（如全反式视黄酸，ATRA）在皮肤稳态和皮肤免疫反应中发挥着重要作用。此外，在各种皮肤疾病中发现视黄酸信号传导失调。本研究通过在小鼠皮肤表面涂抹视黄酸受体（RAR）α和γ和视黄醛-X 受体（RXR）的选择性激动剂和拮抗剂，持续两周，以确定视黄酸受体亚型在皮肤基因调控中的作用。我们观察到，ATRA 和 RARγ 和 RXR 的合成激动剂的应用会导致明显的表皮过度增殖。ATRA 和 RARγ 激动剂进一步增加了视黄酸靶基因（Rbp1、Crabp2、Krt4、Cyp26a1、Cyp26b1）和趋化因子 Ccl17 和 Ccl22 的表达。相比之下，RARα 激动剂强烈降低了 ATRA 合成酶、视黄酸靶基因、皮肤稳态标志物和皮肤中各种细胞因子的表达，从而与 RXR 和 RAR 拮抗剂诱导的表达谱非常相似。我们的研究结果表明，RARα 和 RARγ 亚型在皮肤中具有不同的作用，可能对视黄酸在皮肤中的内源性信号转导的自动调节具有重要意义。我们认为，RXR、RARα 和/或 RARγ 介导的皮肤视黄酸信号转导失调可能会促进皮肤炎症和皮肤屏障功能失调。
