Foxa2 programs Th2 cell-mediated innate immunity in the developing lung.
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-4Ralpha 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.
Chen
Gang
G
Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Wan
Huajing
H
Luo
Fengming
F
Zhang
Liqian
L
Xu
Yan
Y
Lewkowich
Ian
I
Wills-Karp
Marsha
M
Whitsett
Jeffrey A
JA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D020397:Goblet Cells / Q000166:cytology; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D018928:Immunity, Mucosal / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000254:growth & development* / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018418:Th2 Cells / Q000276:immunology*
C496503:Foxa2 protein, mouse; D012333:RNA, Messenger; D051542:Hepatocyte Nuclear Factor 3-beta