Laboratory of Nutritional Bioactivation and Bioanalysis, Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.
PLoS One. 2013 Aug 15;8(8):e71244. doi: 10.1371/journal.pone.0071244. eCollection 2013.
Nuclear receptor-mediated signaling via RARs and PPARδ is involved in the regulation of skin homeostasis. Moreover, activation of both RAR and PPARδ was shown to alter skin inflammation. Endogenous all-trans retinoic acid (ATRA) can activate both receptors depending on specific transport proteins: Fabp5 initiates PPARδ signaling whereas Crabp2 promotes RAR signaling. Repetitive topical applications of ovalbumin (OVA) in combination with intraperitoneal injections of OVA or only intraperitoneal OVA applications were used to induce allergic dermatitis. In our mouse model, expression of IL-4, and Hbegf increased whereas expression of involucrin, Abca12 and Spink5 decreased in inflamed skin, demonstrating altered immune response and epidermal barrier homeostasis. Comprehensive gene expression analysis showed alterations of the cutaneous retinoid metabolism and retinoid-mediated signaling in allergic skin immune response. Notably, ATRA synthesis was increased as indicated by the elevated expression of retinaldehyde dehydrogenases and increased levels of ATRA. Consequently, the expression pattern of genes downstream to RAR was altered. Furthermore, the increased ratio of Fabp5 vs. Crabp2 may indicate an up-regulation of the PPARδ pathway in allergen-induced dermatitis in addition to the altered RAR signaling. Thus, our findings suggest that ATRA levels, RAR-mediated signaling and signaling involved in PPARδ pathways are mainly increased in allergen-induced dermatitis and may contribute to the development and/or maintenance of allergic skin diseases.
核受体介导的视黄酸受体 (RARs) 和过氧化物酶体增殖物激活受体 δ (PPARδ) 信号通路参与皮肤稳态的调节。此外，RAR 和 PPARδ 的激活被证明可以改变皮肤炎症。内源性全反式视黄酸 (ATRA) 可以根据特定的转运蛋白激活这两种受体：Fabp5 起始 PPARδ 信号通路，而 Crabp2 则促进 RAR 信号通路。反复局部应用卵清蛋白 (OVA) 结合腹腔内注射 OVA 或仅腹腔内 OVA 应用被用于诱导过敏性皮炎。在我们的小鼠模型中，在炎症皮肤中，IL-4 和 Hbegf 的表达增加，而 involucrin、Abca12 和 Spink5 的表达减少，表明免疫反应和表皮屏障稳态发生改变。全面的基因表达分析显示，皮肤类视黄醇代谢和类视黄醇介导的信号通路在过敏性皮肤免疫反应中发生改变。值得注意的是，ATRA 合成增加，表明视黄醛脱氢酶的表达升高和 ATRA 水平升高。因此，RAR 下游基因的表达模式发生改变。此外，Fabp5 与 Crabp2 的比值增加可能表明，除了改变的 RAR 信号通路外，过敏原诱导的皮炎中 PPARδ 通路也被上调。因此，我们的研究结果表明，在过敏原诱导的皮炎中，ATRA 水平、RAR 介导的信号通路和参与 PPARδ 途径的信号通路主要增加，并可能有助于过敏性皮肤病的发展和/或维持。
