Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
Department of Dermatology, School of Medicine, Sapporo Medical University, Sapporo, Japan.
Immun Inflamm Dis. 2021 Sep;9(3):734-745. doi: 10.1002/iid3.427. Epub 2021 Apr 1.
Barrier disruption and an excessive immune response in keratinocytes are now considered to have important roles in the pathophysiology of atopic dermatitis (AD). Furthermore, disturbed keratinocyte differentiation is considered to underlie AD. ΔNp63, a p53-like transcription factor, is a major regulator of keratinocyte differentiation. However, the functional significance of ΔNp63 in AD has not been clarified.
In this study, we aimed to investigate the influence of the type 2 inflammatory environment on ΔNp63 expression and AD-associated molecules regulated by ΔNp63 in keratinocytes.
The immunohistochemical expression profiles of ΔNp63 and AD-related molecules were evaluated in human skin tissue. The function of ΔNp63 in the regulation of AD-related molecules and the influence of the type 2 inflammatory environment on ΔNp63 expression were investigated using human primary keratinocytes. Expression of ΔNp63 was manipulated using the RNA interfering method.
In healthy skin tissue, we observed an inverse expression pattern between ∆Np63 and some barrier-related proteins including filaggrin, caspase-14, claudin-1, and claudin-4. ΔNp63 regulated expression of these genes and proteins. In addition, production of IL-1β and IL-33, pro-inflammatory cytokines, was modulated by ΔNp63. Furthermore, prolonged IL-13 exposure increased the thickness of the three-dimensional culture of keratinocytes. IL-13 interfered with ΔNp63 downregulation during calcium-induced keratinocyte differentiation. IL-13 modulated some barrier-related and inflammation-related molecules, which were regulated by ΔNp63.
We have shown that ΔNp63 modulated AD-related barrier and inflammatory molecules. In addition, ΔNp63 expression was affected by IL-4/IL-13. IL-13-ΔNp63 axis would integrate two major factors of AD pathogenesis: dysregulated barrier and inflammation.
目前认为角质形成细胞的屏障破坏和过度免疫反应在特应性皮炎（AD）的病理生理学中起重要作用。此外，角质形成细胞分化障碍被认为是 AD 的基础。ΔNp63 是一种 p53 样转录因子，是角质形成细胞分化的主要调节剂。然而，ΔNp63 在 AD 中的功能意义尚未阐明。
本研究旨在探讨 2 型炎症环境对角质形成细胞中 ΔNp63 表达和 AD 相关分子的影响。
评估人皮肤组织中 ΔNp63 和 AD 相关分子的免疫组织化学表达谱。使用人原代角质形成细胞研究 ΔNp63 在 AD 相关分子调节中的作用和 2 型炎症环境对 ΔNp63 表达的影响。采用 RNA 干扰方法操纵 ΔNp63 的表达。
在健康皮肤组织中，我们观察到 ΔNp63 与一些屏障相关蛋白（包括丝聚合蛋白、半胱氨酸蛋白酶 14、闭合蛋白 1 和闭合蛋白 4）的表达呈负相关。ΔNp63 调节这些基因和蛋白的表达。此外，促炎细胞因子白细胞介素-1β（IL-1β）和白细胞介素-33（IL-33）的产生也受 ΔNp63 调节。此外，IL-13 延长暴露会增加三维培养角质形成细胞的厚度。IL-13 干扰了钙诱导的角质形成细胞分化过程中 ΔNp63 的下调。IL-13 调节了一些由 ΔNp63 调节的屏障相关和炎症相关分子。
我们表明 ΔNp63 调节 AD 相关的屏障和炎症分子。此外，ΔNp63 的表达受 IL-4/IL-13 的影响。IL-13-ΔNp63 轴将整合 AD 发病机制的两个主要因素：失调的屏障和炎症。
