School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA.
Biomedical Research Model Services, University of Wisconsin, Madison, WI 53705, USA.
Int J Mol Sci. 2023 Jun 16;24(12):10241. doi: 10.3390/ijms241210241.
Atopic dermatitis (AD) is a chronic inflammatory skin disease featuring skin barrier dysfunction and immune dysregulation. Previously, we reported that the retinoid-related orphan nuclear receptor RORα was highly expressed in the epidermis of normal skin. We also found that it positively regulated the expression of differentiation markers and skin barrier-related genes in human keratinocytes. In contrast, epidermal RORα expression was downregulated in the skin lesions of several inflammatory skin diseases, including AD. In this study, we generated mouse strains with epidermis-specific ablation to understand the roles of epidermal RORα in regulating AD pathogenesis. Although deficiency did not cause overt macroscopic skin abnormalities at the steady state, it greatly amplified MC903-elicited AD-like symptoms by intensifying skin scaliness, increasing epidermal hyperproliferation and barrier impairment, and elevating dermal immune infiltrates, proinflammatory cytokines, and chemokines. Despite the normal appearance at the steady state, -deficient skin showed microscopic abnormalities, including mild epidermal hyperplasia, increased TEWL, and elevated mRNA expression of , , and genes, indicating subclinical impairment of epidermal barrier functions. Our results substantiate the importance of epidermal RORα in partially suppressing AD development by maintaining normal keratinocyte differentiation and skin barrier function.
特应性皮炎（AD）是一种慢性炎症性皮肤疾病，其特征为皮肤屏障功能障碍和免疫失调。此前，我们曾报道维 A 酸受体相关孤儿核受体 RORα在正常皮肤表皮中高度表达。我们还发现它可正向调控人角质形成细胞中分化标志物和皮肤屏障相关基因的表达。相反，表皮 RORα在包括 AD 在内的几种炎症性皮肤病的皮损中表达下调。在这项研究中，我们构建了表皮特异性敲除的小鼠品系，以了解表皮 RORα在调控 AD 发病机制中的作用。尽管在稳态下缺失不会引起明显的宏观皮肤异常，但它通过增强皮肤鳞屑形成、增加表皮过度增殖和屏障损伤，以及提高真皮免疫浸润、促炎细胞因子和趋化因子，极大地放大了 MC903 诱导的 AD 样症状。尽管在稳态下皮肤外观正常，但 -/- 皮肤表现出微观异常，包括轻度表皮增生、TEWL 增加和 、 和 基因的 mRNA 表达升高，表明表皮屏障功能的亚临床损伤。我们的结果证实了表皮 RORα在通过维持正常角质形成细胞分化和皮肤屏障功能来部分抑制 AD 发展方面的重要性。
