Departments of Dermatology, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13921-6. doi: 10.1073/pnas.1307321110. Epub 2013 Aug 5.
Transgenic mice expressing the mouse interleukin 33 (IL-33) gene driven by a keratin 14 promoter were generated. The skin-selective expression of the IL-33 gene was enhanced, and intense immunofluorescence for IL-33 was evident in the nuclei of the epidermis. Spontaneous itchy dermatitis developed in those mice at 6-8 wk of age in specific pathogen-free conditions. In the lesional skin, the epidermis was thickened and the eosinophils were infiltrated with increased expression of the eosinophil peroxidase and major basic protein genes. Mast cells were also abundant there, and blood histamine and total IgE levels were high. Those phenotypes closely resemble the features of atopic dermatitis. In peripheral blood and lesional skin, IL-5, IL-13, regulated upon activation, normally T-expressed, and presumably secreted (RANTES)/CCL5, and Eotaxin 1/CCL11 were increased, whereas TNF-α, IFN-γ, and thymic stromal lymphopoietin (TSLP) were unaltered. Furthermore, the proportion of group 2 innate lymphoid cells (ILC2s), which produce IL-5, were significantly increased in the lesional skin, peripheral blood, and regional lymph nodes. The dermatitis with eosinophil infiltration was improved by the administration of an anti-IL-5 antibody. These results suggest that the expression of IL-33 in the skin activates an immune response involving ILC2 and that this process might play a crucial role in the pathogenesis of allergic inflammation that is characteristic of atopic dermatitis.
转染了由角蛋白 14 启动子驱动的小鼠白细胞介素 33（IL-33）基因的转基因小鼠被成功构建。这种基因在皮肤中的表达得到了增强，并且在表皮细胞核中可以明显观察到 IL-33 的免疫荧光。在无特定病原体条件下，这些小鼠在 6-8 周龄时自发出现瘙痒性皮炎。在病变皮肤中，表皮增厚，嗜酸性粒细胞浸润，同时嗜酸性粒细胞过氧化物酶和主要碱性蛋白基因的表达增加。那里也有大量的肥大细胞，并且血液中的组胺和总 IgE 水平升高。这些表型与特应性皮炎的特征非常相似。在外周血和病变皮肤中，IL-5、IL-13、激活调节正常 T 细胞表达和分泌因子（RANTES）/CCL5 和嗜酸性粒细胞趋化因子 1/CCL11 增加，而 TNF-α、IFN-γ 和胸腺基质淋巴细胞生成素（TSLP）则没有改变。此外，在病变皮肤、外周血和局部淋巴结中，产生 IL-5 的 2 型固有淋巴细胞（ILC2）的比例显著增加。嗜酸性粒细胞浸润性皮炎通过给予抗 IL-5 抗体得到改善。这些结果表明，皮肤中 IL-33 的表达激活了涉及 ILC2 的免疫反应，并且该过程可能在特应性皮炎特有的过敏炎症发病机制中发挥关键作用。
