School of Pharmacy, The University of Wisconsin, Madison, WI 53705, USA.
Carbone Cancer Center, The University of Wisconsin, Madison, WI 53705, USA.
Int J Mol Sci. 2024 Oct 4;25(19):10698. doi: 10.3390/ijms251910698.
The skin epidermis provides a barrier that is imperative for preventing transepidermal water loss (TEWL) and protecting against environmental stimuli. The underlying molecular mechanisms for regulating barrier functions and sustaining its integrity remain unclear. RORα is a nuclear receptor highly expressed in the epidermis of normal skin. Clinical studies showed that the epidermal RORα expression is significantly reduced in the lesions of multiple inflammatory skin diseases. In this study, we investigate the central roles of RORα in stabilizing skin barrier function using mice with an epidermis-specific gene deletion (). While lacking spontaneous skin lesions or dermatitis, mice exhibited an elevated TEWL rate and skin characteristics of barrier dysfunction. Immunostaining and Western blot analysis revealed low levels of cornified envelope proteins in the epidermis, suggesting disturbed late epidermal differentiation. In addition, an RNA-seq analysis showed the altered expression of genes related to "keratinization" and "lipid metabolism" in RORα deficient epidermis. A lipidomic analysis further uncovered an aberrant ceramide composition in the epidermis. Importantly, epidermal ablation greatly exaggerated percutaneous allergic inflammatory responses to oxazolone in an allergic contact dermatitis (ACD) mouse model. Our results substantiate the essence of epidermal RORα in maintaining late keratinocyte differentiation and normal barrier function while suppressing cutaneous inflammation.
皮肤表皮提供了一道屏障，对于防止经表皮水分流失（TEWL）和防止环境刺激至关重要。然而，调节屏障功能和维持其完整性的潜在分子机制尚不清楚。RORα 是一种在正常皮肤表皮中高度表达的核受体。临床研究表明，多种炎症性皮肤病皮损中表皮 RORα 的表达显著降低。在这项研究中，我们使用表皮特异性基因缺失（）的小鼠来研究 RORα 在稳定皮肤屏障功能中的核心作用。虽然缺乏自发性皮肤损伤或皮炎，但 小鼠表现出 TEWL 率升高和皮肤屏障功能障碍的特征。免疫染色和 Western blot 分析显示， 表皮中的角蛋白包膜蛋白水平较低，表明晚期表皮分化受到干扰。此外，RNA-seq 分析显示 RORα 缺失表皮中与“角质化”和“脂质代谢”相关的基因表达发生改变。脂质组学分析进一步揭示了 表皮中异常的神经酰胺组成。重要的是，表皮 缺失极大地加剧了 oxazolone 诱导的变应性接触性皮炎（ACD）小鼠模型中的经皮过敏炎症反应。我们的研究结果证实了表皮 RORα 在维持晚期角质形成细胞分化和正常屏障功能的同时抑制皮肤炎症方面的重要作用。
