Foxa2 Programs Th2 Cell-Mediated Innate Immunity in the Developing Lung

被引:71
作者
Chen, Gang
Wan, Huajing [3 ]
Luo, Fengming [4 ]
Zhang, Liqian
Xu, Yan
Lewkowich, Ian [2 ]
Wills-Karp, Marsha [2 ]
Whitsett, Jeffrey A. [1 ]
机构
[1] Childrens Hosp, Med Ctr, Div Pulm Biol, Sect Neonatol Perinatal & Pulm Biol,Perinatal Ins, Cincinnati, OH 45229 USA
[2] Univ Cincinnati, Coll Med, Div Immunobiol, Cincinnati, OH 45220 USA
[3] Sichuan Univ, Univ Hosp 2, W China Dev & Stem Cell Inst, Chengdu 610064, Peoples R China
[4] Sichuan Univ, W China Hosp, Chengdu 610064, Peoples R China
基金
美国国家卫生研究院;
关键词
ACTIVATION-REGULATED CHEMOKINE; ACIDIC MAMMALIAN CHITINASE; AIRWAY EPITHELIAL-CELLS; GROWTH-FACTOR RECEPTOR; DENDRITIC CELLS; IL-4; RECEPTOR; SIGNALING PATHWAYS; ASTHMA; RESPONSES; INFLAMMATION;
D O I
10.4049/jimmunol.1000223
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:6133 / 6141
页数:9
相关论文
共 59 条
[51]   Sox2 Is Required for Maintenance and Differentiation of Bronchiolar Clara, Ciliated, and Goblet Cells [J].
Tompkins, David H. ;
Besnard, Valerie ;
Lange, Alexander W. ;
Wert, Susan E. ;
Keiser, Angela R. ;
Smith, April N. ;
Lang, Richard ;
Whitsett, Jeffrey A. .
PLOS ONE, 2009, 4 (12)
[52]   Distinct Temporal Requirements for the Homeobox Gene Gsx2 in Specifying Striatal and Olfactory Bulb Neuronal Fates [J].
Waclaw, Ronald R. ;
Wang, Bei ;
Pei, Zhenglei ;
Ehrman, Lisa A. ;
Campbell, Kenneth .
NEURON, 2009, 63 (04) :451-465
[53]   Foxa2 is required for transition to air breathing at birth [J].
Wan, HJ ;
Xu, Y ;
Ikegami, M ;
Stahlman, MT ;
Kaestner, KH ;
Ang, SL ;
Whitsett, JA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (40) :14449-14454
[54]   Foxa2 regulates alveolarization and goblet cell hyperplasia [J].
Wan, HJ ;
Kaestner, KH ;
Ang, SL ;
Ikegami, M ;
Finkelman, FD ;
Stahlman, MT ;
Fulkerson, PC ;
Rothenberg, ME ;
Whitsett, JA .
DEVELOPMENT, 2004, 131 (04) :953-964
[55]   Interleukin-13: Central mediator of allergic asthma [J].
Wills-Karp, M ;
Luyimbazi, J ;
Xu, XY ;
Schofield, B ;
Neben, TY ;
Karp, CL ;
Donaldson, DD .
SCIENCE, 1998, 282 (5397) :2258-2261
[56]   Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin [J].
Yang, M ;
Hogan, SP ;
Henry, PJ ;
Matthaei, KI ;
McKenzie, ANJ ;
Young, IG ;
Rothenberg, ME ;
Foster, PS .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2001, 25 (04) :522-530
[57]   IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production [J].
Zhen, Guohua ;
Park, Sung Woo ;
Nguyenvu, Louis T. ;
Rodriguez, Madeleine W. ;
Barbeau, Rebecca ;
Paquet, Agnes C. ;
Erle, David J. .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2007, 36 (02) :244-253
[58]   Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation [J].
Zhu, Z ;
Zheng, T ;
Homer, RJ ;
Kim, YK ;
Chen, NY ;
Cohn, L ;
Hamid, Q ;
Elias, JA .
SCIENCE, 2004, 304 (5677) :1678-1682
[59]   Chemokines in asthma: Cooperative interaction between chemokines and IL-13 [J].
Zimmermann, N ;
Hershey, GK ;
Foster, PS ;
Rothenberg, ME .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2003, 111 (02) :227-242