Djalilian Ali R, McGaughey David, Patel Satyakam, Seo Eun Young, Yang Chenghua, Cheng Jun, Tomic Melanija, Sinha Satrajit, Ishida-Yamamoto Akemi, Segre Julia A
National Human Genome Research Institute, National Eye Institute, and National Institute of Child Health and Development, NIH, Bethesda, Maryland 20892, USA.
J Clin Invest. 2006 May;116(5):1243-53. doi: 10.1172/JCI27186. Epub 2006 Apr 20.
Inflammatory skin disorders result in significant epidermal changes, including keratinocyte hyperproliferation, incomplete differentiation, and impaired barrier. Here we test whether, conversely, an impaired epidermal barrier can promote an inflammatory response. Mice lacking the transcription factor Kruppel-like factor 4 (Klf4) have a severe defect in epidermal barrier acquisition. Transcription profiling of Klf4(-/-) newborn skin revealed similar changes in gene expression to involved psoriatic plaques, including a significant upregulation of the gap junction protein connexin 26 (Cx26). Ectopic expression of Cx26 from the epidermis-specific involucrin (INV) promoter (INV-Cx26) demonstrated that downregulation of Cx26 is required for barrier acquisition during development. In juvenile and adult mice, persistent Cx26 expression kept wounded epidermis in a hyperproliferative state, blocked the transition to remodeling, and led to an infiltration of immune cells. Mechanistically, ectopic expression of Cx26 in keratinocytes resulted in increased ATP release, which delayed epidermal barrier recovery and promoted an inflammatory response in resident immune cells. These results provide a molecular link between barrier acquisition in utero and epidermal remodeling after wounding. More generally, these studies suggest that the most effective treatments for inflammatory skin disorders might concomitantly suppress the immune response and enhance epidermal differentiation to restore the barrier.
炎症性皮肤病会导致显著的表皮变化，包括角质形成细胞过度增殖、分化不完全以及屏障功能受损。在此，我们测试相反的情况，即表皮屏障受损是否会促进炎症反应。缺乏转录因子Kruppel样因子4（Klf4）的小鼠在表皮屏障形成方面存在严重缺陷。对Klf4（-/-）新生小鼠皮肤进行转录谱分析发现，其基因表达变化与银屑病斑块相似，包括缝隙连接蛋白连接蛋白26（Cx26）显著上调。从表皮特异性内披蛋白（INV）启动子异位表达Cx26（INV-Cx26）表明，发育过程中屏障形成需要下调Cx26。在幼年和成年小鼠中，持续的Cx26表达使受伤的表皮保持过度增殖状态，阻止其向重塑阶段转变，并导致免疫细胞浸润。从机制上讲，角质形成细胞中Cx26的异位表达导致ATP释放增加，这延迟了表皮屏障的恢复，并促进了驻留免疫细胞的炎症反应。这些结果在子宫内屏障形成与受伤后表皮重塑之间建立了分子联系。更普遍地说，这些研究表明，治疗炎症性皮肤病最有效的方法可能是同时抑制免疫反应并增强表皮分化以恢复屏障功能。
