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

PLoS One. 2019 Dec 27;14(12):e0226517. doi: 10.1371/journal.pone.0226517. eCollection 2019.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / chemically induced
  • Asthma / genetics
  • Asthma / immunology
  • Asthma / microbiology*
  • Cell Line
  • Disease Models, Animal
  • Escherichia coli Infections / genetics
  • Escherichia coli Infections / metabolism
  • Escherichia coli Infections / prevention & control*
  • Female
  • Gene Deletion
  • Gene Expression Regulation
  • Hepatocyte Nuclear Factor 3-beta / genetics*
  • Humans
  • Mice
  • Ovalbumin / adverse effects
  • Th2 Cells / metabolism
  • beta-Defensins / metabolism*

Substances

  • Defb1 protein, mouse
  • Foxa2 protein, mouse
  • beta-Defensins
  • Hepatocyte Nuclear Factor 3-beta
  • Ovalbumin

Grant support

This work was supported by the National Natural Science Foundation of China (no. 81770072; no. 81470268), National Key R&D Program of China (no. 2017YFC0107805) and Sichuan Science and Technology Support Project (no. 2016GFW0175; no. 2016SZ0002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.