Molecular characterization of pulmonary defenses against bacterial invasion in allergic asthma: The role of Foxa2 in regulation of β-defensin 1

Autoři: Chuanqi Wei aff001;  Xiaoju Tang aff001;  Faping Wang aff001;  Yan Li aff001;  Lin Sun aff001;  Fengming Luo aff001
Působiště autorů: Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Guo Xue Xiang, Chengdu, China aff001
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226517


Allergic asthma, characterized by chronic airway Th2-dominated inflammation, is associated with an increased risk of infection; however, the underlying mechanisms are unclear. Forkhead box protein A2 (Foxa2) plays a critical role in Th2 inflammation and is associated with pulmonary defenses. To determining the role of Foxa2 in Th2-dominated lung inflammation against the invading bacteria, we established a mouse OVA-sensitized model, an Escherichia coli lung invasion model, and mice with conditional deletion of Foxa2 in respiratory epithelial cells. The number of bacteria in the lung tissue was counted to assess clearance ability of lung. Lung inflammation and histopathology was evaluated using HE and PAS staining. It was found that OVA-sensitized mice had decreased E. coli clearance, reduced Foxa2 expression, and decreased DEFB1 secretion. Conditional deletion of Foxa2 in respiratory epithelial cells led to decreased clearance of E. coli and impaired secretion of DEFB1, similar to the OVA-induced allergic condition. The impaired secretion of DEFB1 may be responsible for the increased risk of infection in the Th2-dominated airway inflammation. Dual luciferase assay demonstrated that Foxa2 regulates DEFB1 expression by affecting its promoter activity in HBE cells. Our study indicated that Foxa2 plays an important role in Th2-dominated airway inflammation against invading bacteria. Conditional deletion of Foxa2 in respiratory epithelial cells can reduce pulmonary’s defense against bacterial invasion by inhibiting DEFB1expression.

Klíčová slova:

Asthma – Enzyme-linked immunoassays – Epithelial cells – Gene expression – Inflammation – Luciferase – Secretion – Transfection


1. Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma. 2018. (Accessed August 21th, 2019).

2. Li J, Sun B, Huang Y, Lin X, Zhao D, Tan G, et al. A multicentre study assessing the prevalence of sensitizations in patients with asthma and/or rhinitis in China. Allergy. 2009,64:1083–92. doi: 10.1111/j.1398-9995.2009.01967.x 19210346

3. Helby J, Nordestgaard BG, Benfield T, Bojesen SE. Asthma, other atopic conditions and risk of infections in 105 519 general population never and ever smokers. J Intern Med. 2017,282:254–267. doi: 10.1111/joim.12635 28547823

4. Almirall J, Bolíbar I, Serra-Prat M, Roig J, Hospital I, Carandell E, et al. New evidence of risk factors for community-acquired pneumonia: a population-based study. Eur Respir J. 2008,31: 1274–84. doi: 10.1183/09031936.00095807 18216057

5. Colak Y, Afzal S, Nordestgaard BG, Lange P. Characteristics and Prognosis of Never-Smokers and Smokers with Asthma in the Copenhagen General Population Study. A Prospective Cohort Study. Am J Respir Crit Care Med. 2015,192: 172–81. doi: 10.1164/rccm.201502-0302OC 25914942

6. Beisswenger C, Kandler K, Hess C, Garn H, Felgentreff K, Wegmann M, et al. Allergic airway inflammation inhibits pulmonary antibacterial host defense. J Immunol. 2006,177:1833–7. doi: 10.4049/jimmunol.177.3.1833 16849494

7. Kang CI, Rouse MS, Patel R, Kita H, Juhn YJ. Allergic airway inflammation and susceptibility to pneumococcal pneumonia in a murine model with real-time in vivo evaluation. Clin Exp Immunol. 2009, 156:552–61. doi: 10.1111/j.1365-2249.2009.03925.x 19438610

8. Eisele NA, Anderson DM. Host Defense and the Airway Epithelium: Frontline Responses That Protect against Bacterial Invasion and Pneumonia. J Pathog. 2011, 2011:249802. doi: 10.4061/2011/249802 22567325

9. Giamarellos-Bourboulis EJ, Platzer M, Karagiannidis I, Kanni T, Nikolakis G, Ulrich J, et al. High Copy Numbers of β-Defensin Cluster on 8p23.1, Confer Genetic Susceptibility, and Modulate the Physical Course of Hidradenitis Suppurativa/Acne Inversa. J Invest Dermatol. 2016,136:1592–1598. doi: 10.1016/j.jid.2016.04.021 27164300

10. Nurjadi D, Herrmann E, Hinderberger I, Zanger P. Impaired β-defensin expression in human skin links DEFB1 promoter polymorphisms with persistent Staphylococcus aureus nasal carriage. J Infect Dis. 2013,207:666–74. doi: 10.1093/infdis/jis735 23204181

11. Singh PK, Jia HP, Wiles K, Hesselberth J, Liu L, Conway BA, et al. Production of beta-defensins by human airway epithelia. Proc Natl Acad Sci USA. 1998,95:14961–6. doi: 10.1073/pnas.95.25.14961 9843998

12. Tomalka J, Azodi E, Narra HP, Patel K, O'Neill S, Cardwell C, et al.β-Defensin 1 plays a role in acute mucosal defense against Candida albicans. J Immunol. 2015,194:1788–95. doi: 10.4049/jimmunol.1203239 25595775

13. Moser C, Weiner DJ, Lysenko E, Bals R, Weiser JN, Wilson JM. Wilson. beta-Defensin 1 contributes to pulmonary innate immunity in mice. Infect.Immun. 2002, 70: 3068–3072. doi: 10.1128/IAI.70.6.3068-3072.2002 12010999

14. Ryan LK, Wu J, Schwartz K, Yim S, Diamond G.β-Defensins Coordinate In Vivo to Inhibit Bacterial Infections of the Trachea. Vaccines (Basel). 2018,6. pii: E57.

15. Taggart CC, Greene CM, Smith SG, Levine RL, McCray PB Jr, O'Neill S, McElvaney NG. Inactivation of human beta-defensins 2 and 3 by elastolytic cathepsins. J Immunol. 2003,171:931–7. doi: 10.4049/jimmunol.171.2.931 12847264

16. Leung TF, Li CY, Liu EK, Tang NL, Chan IH, Yung E, et al. Asthma and atopy are associated with DEFB1 polymorphisms in Chinese children. Genes Immun. 2006,7:59–64. doi: 10.1038/sj.gene.6364279 16435024

17. Baines KJ, Wright TK, Simpson JL, McDonald VM, Wood LG, Parsons KS, et al. Airway β-Defensin-1 Protein Is Elevated in COPD and Severe Asthma. Mediators Inflamm. 2015, 407271. doi: 10.1155/2015/407271 26568662

18. Wan H, Xu Y, Ikegami M, Stahlman MT, Kaestner KH, Ang SL, Whitsett JA. Foxa2 is required for transition to air breathing at birth. Proc Natl Acad Sci USA. 2004,101:14449–54. doi: 10.1073/pnas.0404424101 15452354

19. Chen G, Wan H, Luo F, Zhang L, Xu Y, Lewkowich I, et al. Foxa2 programs Th2 cell-mediated innate immunity in the developing lung. J Immunol. 2010,184:6133–41. doi: 10.4049/jimmunol.1000223 20483781

20. Park SW, Verhaeghe C, Nguyenvu LT, Barbeau R, Eisley CJ, Nakagami Y, et al. Distinct roles of FOXA2 and FOXA3 in allergic airway disease and asthma. Am J Respir Crit Care Med. 2009, 180:603–10. doi: 10.1164/rccm.200811-1768OC 19628779

21. Tang X, Liu XJ, Tian C, Su Q, Lei Y, Wu Q, et al. Foxa2 regulates leukotrienes to inhibit Th2-mediated pulmonary inflammation. Am J Respir Cell Mol Biol. 2013, 49:960–70. doi: 10.1165/rcmb.2013-0122OC 23822876

22. Tang X, Sun L, Jin X, Chen Y, Zhu H, Liang Y, et al. Runt-Related Transcription Factor 1 Regulates LPS-Induced Acute Lung Injury via NF-κB Signaling. Am J Respir Cell Mol Biol. 2017, 57:174–183. doi: 10.1165/rcmb.2016-0319OC 28314106

23. Peyrin-Biroulet L, Beisner J, Wang G, Nuding S, Oommen ST, Kelly D, et al. Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc Natl Acad Sci U S A. 2010,107(19):8772–7. doi: 10.1073/pnas.0905745107 20421464

24. Choi W, Yang AX, Waltenburg MA. FOXA2 depletion leads to mucus hypersecretion in canine airways with respiratory diseases. Cell Microbiol. 2018, 16: e12957.

25. Valore EV, Park CH, Quayle AJ, Wiles KR, McCray PB Jr, Ganz T. Human b-defensin-1: an antimicrobial peptide of urogenital tissues. J. Clin. Invest. 1998,101: 1633–42. doi: 10.1172/JCI1861 9541493

26. Zhao C, Wang I, Lehrer RI. Widespread expression of beta-defensin hBD-1 in human secretory glands and epithelial cells. FEBS Lett.1996,396:319–22. doi: 10.1016/0014-5793(96)01123-4 8915011

27. Kumar V, Everingham S, Hall C, Greer PA, Craig AW. Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model. Eur J Immunol. 2014,44:831–41. doi: 10.1002/eji.201343757 24375267

28. Morrison GM, Davidson DJ, Kilanowski FM, Borthwick DW, Crook K, Maxwell AI, et al. Mouse beta defensin-1 is a functional homolog of human beta defensin-1. Mamm Genome. 1998, 9:453–7. doi: 10.1007/s003359900795 9585433

Článek vyšel v časopise


2019 Číslo 12