Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice
Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice
复制标题
DOI：
10.1073/pnas.1307321110
复制
发表时间：
2013-08-20
影响因子：
11.1
通讯作者：
Yamanishi, Kiyofumi
中科院分区：
文献类型：
--
作者：
Imai, Yasutomo;Yasuda, Koubun;Yamanishi, Kiyofumi
产生了由角蛋白14启动子驱动表达小鼠白细胞介素33 （IL-33）基因的转基因小鼠。IL-33基因的皮肤选择性表达增强，IL-33的免疫荧光在表皮细胞核中明显增强。在特定的无病原体条件下，这些小鼠在6-8周龄时发生自发性瘙痒性皮炎。病变皮肤表皮增厚，嗜酸性细胞浸润，嗜酸性细胞过氧化物酶和主要碱性蛋白基因表达增加。那里也有大量的肥大细胞，血液组胺和总IgE水平很高。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，激活后调节的IL-5、IL-13、正常t表达和推测分泌(RANTES)/CCL5和Eotaxin 1/CCL11升高，而tnf - α、ifn - γ和胸腺基质淋巴生成素（TSLP）不变。此外，产生IL-5的2组先天淋巴样细胞（ILC2s）在病变皮肤、外周血和区域淋巴结中的比例显著增加。抗il -5抗体可改善嗜酸性粒细胞浸润的皮炎。这些结果表明，IL-33在皮肤中的表达激活了涉及ILC2的免疫反应，这一过程可能在过敏性炎症的发病机制中起关键作用，这是特应性皮炎的特征。
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-alpha, IFN-gamma, 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.