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Critical roles of Foxa2 and Spdef in regulating innate immunity and goblet cell differentiation in the lung

Chen, Gang
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1276537438

Abstract Details

2010, PhD, University of Cincinnati, Medicine : Molecular and Developmental Biology.
The respiratory epithelial cells lining the conducting airways play critical roles in mediating innate and acquired immune responses by participating mucociliary clearance, secreting anti-bacterial peptides, and release cytokines and chemokines to interact with immune cells. The forkhead box transcription factor, Foxa2, is normally expressed in respiratory epithelial cells lining conducting airways and in alveolar type II cells. Foxa2 is required for normal lung maturation, surfactant protein and lipid synthesis during lung development. However, the role of Foxa2 in regulating crosstalk between epithelium and immune system during lung development was unknown. In the present thesis, selective deletion of Foxa2 allele in the respiratory epithelium mediated by human surfactant protein C (SFTPC) promoter driven Cre recombinase during embryonic stage (E6.5-E12.5) was found to cause asthma-like phenotype including eosinophilic inflammation and goblet cell metaplasia in the neonatal mice. Loss of Foxa2 induced the recruitment and activation of myeloid dendritic cells (mDCs) and T helper 2 (Th2) cells in the lung, resulting in increased production of Th2 cytokines and chemokines, including interleukin 4 (IL-4), IL-13, IL-5 and thymus and activation-regulated chemokine (Tarc), and induced expression of goblet cell transcription factor Spdef. Expression of Foxa2 in the non-ciliated secretory epithelial cells (Clara cells) inhibited Spdef expression and goblet cell differentiation after allergen exposure, suggesting that Foxa2 and Spdef interacted within a genetic network that was associated with goblet cell differentiation. Spdef, SAM pointed domain Ets-like factor, normally expressed at low level in tracheal and bronchial epithelium, is significantly induced in goblet cells after IL-13 or allergen exposure at a Stat6 dependent manner. Expression of Spdef in Clara cells caused rapid and reversible goblet cell differentiation in the absence of cell proliferation in vivo. Spdef enhanced the expression of genes associated with goblet cell differentiation and pathogenesis of asthma, including Muc16, Agr2, Clca1, Ptger3, Muc5ac, and a group of genes mediating mucin glycosylation, including Gcnt3. Deletion of the murine Spdef gene resulted in the absence of goblet cells in tracheal-laryngeal submucosal glands and in the surface epithelium after pulmonary allergen exposure in vivo, demonstrating its requirement for normal goblet cell differentiation in the lung. Spdef inhibited Foxa2 and TTF-1, and induced Foxa3 demonstrating its pivotal role in transcriptional control of airway epithelial cell differentiation. Spdef and Foxa3 were increased after sensitization with pulmonary allergen and were co-localized in goblet cells in normal human bronchial glands and in goblet cells lining airways of patients with chronic lung diseases. Our current findings provided new evidence that the innate immune system is strongly determined by respiratory epithelial cells during early neonatal period via the transcription factor Foxa2. Loss of Foxa2 induced expression of Spdef that was found to play a critical role in the regulation of a transcriptional network mediating goblet cell differentiation and mucus hyperproduction, a process that is highly relevant to the pathogenesis of asthma, cystic fibrosis, and other inflammatory lung diseases.
Jeffrey Whitsett, MD (Committee Chair)
James Wells, PhD (Committee Member)
George Leikauf, PhD (Committee Member)
Gurjit Hershey, MD, PhD (Committee Member)
John Shannon, PhD (Committee Member)
141 p.
Immunology
Foxa2; Spdef; innate immunity; goblet cell; mucin; lung

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Citations

  • Chen, G. (2010). Critical roles of Foxa2 and Spdef in regulating innate immunity and goblet cell differentiation in the lung [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1276537438

    APA Style (7th edition)

  • Chen, Gang. Critical roles of Foxa2 and Spdef in regulating innate immunity and goblet cell differentiation in the lung. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1276537438.

    MLA Style (8th edition)

  • Chen, Gang. "Critical roles of Foxa2 and Spdef in regulating innate immunity and goblet cell differentiation in the lung." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1276537438

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.