Department of Dermatology, Venerology, and Allergology, Medical University of Innsbruck, Innsbruck, Austria; Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Department of Dermatology and Venerology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Am J Pathol. 2015 Oct;185(10):2777-89. doi: 10.1016/j.ajpath.2015.06.021. Epub 2015 Aug 28.
Tight junctions are important for skin barrier function. The tight junction protein claudin 1 (Cldn-1) has been reported to be down-regulated in nonlesional skin of atopic dermatitis (AD) patients. In contrast, we did not observe a significant down-regulation of Cldn-1 in nonlesional skin of the AD cohort used in this study. However, for the first time, a significant down-regulation of Cldn-1 in the upper and lower epidermal layers of lesional skin was detected. In addition, there was a significant up-regulation of Cldn-4 in nonlesional, but not lesional, AD skin. For occludin, no significant alterations were observed. In an AD-like allergic dermatitis mouse model, Cldn-1 down-regulation in eczema was significantly influenced by dermal inflammation, and significantly correlated with hallmarks of eczema (ie, increased keratinocyte proliferation, altered keratinocyte differentiation, increased epidermal thickness, and impaired barrier function). In human epidermal equivalents, the addition of IL-4, IL-13, and IL-31 resulted in a down-regulation of Cldn-1, and Cldn1 knockdown in keratinocytes resulted in abnormal differentiation. In summary, we provide the first evidence that Cldn-1 and Cldn-4 are differentially involved in AD pathogenesis. Our data suggest a role of Cldn-1 in AD eczema formation triggered by inflammation.
紧密连接对于皮肤屏障功能很重要。已有报道称，在特应性皮炎（AD）患者的非皮损皮肤中，紧密连接蛋白 Claudin-1（Cldn-1）表达下调。然而，在本研究中，我们并未观察到 AD 患者非皮损皮肤中 Cldn-1 的显著下调。但这是首次在皮损皮肤的表皮上层和下层中检测到 Cldn-1 的显著下调。此外，在非皮损但有 AD 皮肤中，Cldn-4 显著上调。而在闭合蛋白（occludin）中，未观察到明显的变化。在 AD 样过敏性皮炎小鼠模型中，湿疹中的 Cldn-1 下调受到真皮炎症的显著影响，并且与湿疹的特征明显相关（即角质形成细胞增殖增加、角质形成细胞分化改变、表皮厚度增加和屏障功能受损）。在人表皮等效物中，添加 IL-4、IL-13 和 IL-31 导致 Cldn-1 下调，角质形成细胞中的 Cldn1 敲低导致异常分化。总之，我们提供了首个证据表明 Cldn-1 和 Cldn-4 参与 AD 发病机制的方式不同。我们的数据提示 Cldn-1 在炎症触发的 AD 湿疹形成中发挥作用。
