Foxa2 Programs Th2 Cell-Mediated Innate Immunity in the Developing Lung
Foxa2 Programs Th2 Cell-Mediated Innate Immunity in the Developing Lung
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DOI：
10.4049/jimmunol.1000223
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发表时间：
2010-06-01
影响因子：
4.4
通讯作者：
Whitsett, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Chen, Gang;Wan, Huajing;Whitsett, Jeffrey A.
出生后，呼吸道通过诱导肺稳态所需的复杂的先天性和获得性免疫系统来适应病原体、过敏原和毒物的反复暴露。在这项研究中，我们表明，Foxa 2，选择性地表达在呼吸道上皮细胞，在调节影响Th 2细胞介导的肺部炎症的遗传程序中起着关键作用。Foxa 2基因编码一种选择性表达于呼吸道上皮细胞的翼状螺旋/叉头盒转录因子，其缺失可引起自发性肺嗜酸性粒细胞炎症和杯状细胞化生。Foxa 2的缺失诱导了肺中髓样树突状细胞和Th 2细胞的募集和活化，导致Th 2细胞因子和趋化因子的产生增加。Foxa 2诱导的调节Th 2细胞介导的炎症和杯状细胞分化的基因表达的丧失，包括IL-13、IL-4、嗜酸性粒细胞趋化因子、胸腺和活化调节趋化因子、IL 33、Ccl 20和含SAM指向结构域的Ets转录因子。通过用抗IL-4 R α亚基的mAb处理新生Foxa 2（Delta/Delta）小鼠来消除肺部炎症和杯状细胞分化。呼吸道上皮在发育中的肺中在由Foxa 2调节的过程中在Th 2介导的炎症和先天免疫的调节中起核心作用。免疫学杂志，2010，184：6133-6141。
After birth, the respiratory tract adapts to recurrent exposures to pathogens, allergens, and toxicants by inducing the complex innate and acquired immune systems required for pulmonary homeostasis. In this study, we show that Foxa2, expressed selectively in the respiratory epithelium, plays a critical role in regulating genetic programs influencing Th2 cell-mediated pulmonary inflammation. Deletion of the Foxa2 gene, encoding a winged helix/forkhead box transcription factor that is selectively expressed in respiratory epithelial cells, caused spontaneous pulmonary eosinophilic inflammation and goblet cell metaplasia. Loss of Foxa2 induced the recruitment and activation of myeloid dendritic cells and Th2 cells in the lung, causing increased production of Th2 cytokines and chemokines. Loss of Foxa2-induced expression of genes regulating Th2 cell-mediated inflammation and goblet cell differentiation, including IL-13, IL-4, eotaxins, thymus and activation-regulated chemokine, Il33, Ccl20, and SAM pointed domain-containing Ets transcription factor. Pulmonary inflammation and goblet cell differentiation were abrogated by treatment of neonatal Foxa2(Delta/Delta) mice with mAb against IL-4R alpha subunit. The respiratory epithelium plays a central role in the regulation of Th2-mediated inflammation and innate immunity in the developing lung in a process regulated by Foxa2. The Journal of Immunology, 2010, 184: 6133-6141.