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Immunity in the Developing Lung Foxa2 Programs Th2 Cell-Mediated Foxa2 Programs Th2 Cell-Mediated Innate Immunity in the Developing Lung Gang Chen, Huajing Wan, Fengming Luo, Liqian Zhang, Yan Xu, Ian Lewkowich, Marsha Wills-Karp and Jeffrey A. This information is current as Whitsett of September 27, 2021. J Immunol 2010; 184:6133-6141; Prepublished online 5 May 2010; doi: 10.4049/jimmunol.1000223 http://www.jimmunol.org/content/184/11/6133 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/05/05/jimmunol.100022 Material 3.DC1 http://www.jimmunol.org/ References This article cites 59 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/184/11/6133.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 27, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Foxa2 Programs Th2 Cell-Mediated Innate Immunity in the Developing Lung Gang Chen,* Huajing Wan,† Fengming Luo,‡ Liqian Zhang,* Yan Xu,* Ian Lewkowich,x Marsha Wills-Karp,x and Jeffrey A. Whitsett* 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 Downloaded from 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 Foxa2Δ/Δ mice with mAb against IL-4Ra 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. http://www.jimmunol.org/ fter birth, the respiratory tract is recurrently exposed to inflammation is dominated by Th2 cell activation and production pathogens, allergens, and toxicants. A multilayered in- of IL-13, IL-4, IL-5, eotaxins, and other mediators that influence A nate and acquired host defense system develops to innate immune responses, Ab production, goblet cell metaplasia, maintain pulmonary homeostasis in the face of these challenges. airway remodeling, and hyperreactivity (5). IL-4 binds to two Th2-dominated inflammation and mucus hyperproduction are distinct receptor complexes, whereas IL-13 only binds to one of common features of acute and chronic pulmonary disorders, in- these complexes. Specifically, IL-4 binds to the IL-4Ra–chain, the cluding asthma. Normally, inflammatory responses are precisely functional receptor subunit of both the type I receptor, which is balanced to achieve mucociliary clearance and removal of a heterodimer of IL-4Ra and the gc-chain, and the type II re- pathogens. Various signaling and transcriptional programs in- ceptor, which is a heterodimer of IL-4Ra and IL-13Ra1. IL-13 by guest on September 27, 2021 fluence allergic lung inflammation and mucus hyperproduction, does not bind to IL-4Ra directly but binds to IL-13Ra1 and can including the IL-4R/STAT6 (1), TLR/NF-kB (2), and epidermal only activate the type II receptor. As the common subunit of re- growth factor receptor/MAPK (3, 4) pathways. Allergen-induced ceptor complexes for both IL-4 and IL-13, IL-4Ra is required for mediating signal transduction of these two cytokines (1, 6, 7). Targeting IL-4Ra function by antagonists or its expression by *Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cin- antisense oligonucleotides suppressed airway Th2 inflammation, cinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; xDivision of hyperresponsiveness, and mucus production after allergen expo- Immunobiology, University of Cincinnati College of Medicine, Cincinnati, OH 45220; †West China Developmental and Stem Cell Institute, Sichuan University sure in vivo (8, 9), indicating the pivotal role of IL-4Ra in me- Second University Hospital, Chengdu; and ‡West China Hospital of Sichuan Univer- diating Th2 response. There is increasing evidence that respiratory sity, Chengdu, People’s Republic of China epithelial cells lining conducting airways play important roles in Received for publication January 29, 2010. Accepted for publication March 25, 2010. modulation of inflammatory responses to allergens, pathogens, This work was supported by the American Lung Association (to H.W.), National and injurious agents (10, 11). Innate immune responses induced Institutes of Health Grants HL095580 and HL090156 (to J.A.W. and Y.X.), and by epithelial cells in response to pathogen are crucial for dendritic National Heart, Lung, and Blood Institute Grant AR47363, which supported the flow cytometry core at Cincinnati Children’s Hospital Medical Center. cells (DCs) to initiate and maintain allergic Th2 cell responses in The sequences presented in this article have been submitted to the National Center experimental asthma (12, 13). Recent studies, from this laboratory for Biotechnology Information Gene Expression Omnibus (www.ncbi.nlm.nih.gov/ and others, demonstrated that expression of Foxa2, a member of geo/query/) under accession number GSE19204. the forkhead box family of transcription factors expressed in Address correspondence and reprint requests to Dr. Jeffrey A. Whitsett at the current the respiratory epithelium, is inhibited during allergen or IL-13– address: Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, MLC7029, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. E-mail address: induced goblet cell metaplasia and Th2 inflammation (14, 15). [email protected] Deletion of Foxa2 in respiratory epithelial cells in the mouse The online version of this article contains supplemental material. impaired surfactant production and lung maturation before birth Abbreviations used in this paper: AHR, airway hyperresponsiveness; a.u., arbitrary and caused spontaneous inflammation and goblet cell metaplasia units; BALF, bronchoalveolar lavage fluid; Chia, acidic chitinase; DC, dendritic cell; after birth, indicating a requirement for Foxa2 in normal postnatal E, embryonic day; EGFP, enhanced GFP; Eos, eosinophil; GO, gene ontology; Lym, lymphocyte; Mac, macrophage; mDC, myeloid dendritic cell; Neu, neutrophil; pDC, pulmonary homeostasis (16). Goblet cell metaplasia induced by plasmacytoid dendritic cell; PN, postnatal day; qRT-PCR, quantitative RT-PCR; allergens or IL-13 was dependent on Stat6 in a process associated Spdef, SAM pointed domain-containing Ets transcription factor; Tarc, thymus and with the induction of SAM pointed domain-containing Ets tran- activation-regulated chemokine. scription factor (Spdef) and Foxa3, indicating that these tran- Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 scription factors interact in a network influencing airway epithelial www.jimmunol.org/cgi/doi/10.4049/jimmunol.1000223 6134 Foxa2 AND Th2-MEDIATED LUNG INFLAMMATION differentiation (14, 17, 18). Recent studies demonstrated that induced at 6 wk of age by provision of doxycycline 24 h before mice were goblet cells induced by pulmonary allergens are derived from the intranasally sensitized with OVA (Supplemental Fig. 8). The control mice differentiation of resident Clara cells that serve as progenitor cells were the single transgenic littermates (Scgb1a1-rtTA) that received the same doxycycline and OVA treatments. Doxycycline was continued until in the bronchiolar epithelium (18, 19). In initial studies, in which the time of sacrifice. Foxa2 was deleted in the respiratory epithelium prior to birth, mucous cell metaplasia, alveolar remodeling, and inflammation mRNA microarray analysis were observed (14). The characteristics and mechanisms un- Lung cRNA was hybridized to the murine genome MOE430 chips (con- derlying lung inflammation caused by loss of Foxa2 in airway sisting of 45,000 gene entries, Affymetrix, Santa Clara, CA) according to epithelial cells are unclear at present. the manufacturer’s protocol. The RNA quality and quantity, probe prep- In this study, we demonstrate that respiratory epithelial cell- aration, labeling,
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