Adenovirus-mediated Foxp3 expression in lung epithelial cells reduces airway inflammation in ovalbumin and cockroach-induced asthma model.

Soojin Park,Hwan-Suck Chung,Hyunil Lee,Dasom Shin,Hyunsu Bae,Junghee Moon,Kyung-Hwa Jung

doi:10.1038/emm.2016.83

Abstract

Foxp3 is a master regulator of CD4+CD25+ regulatory T-cell (Treg) function and is also a suppressor of SKP2 and HER2/ErbB2. There are an increasing number of reports describing the functions of Foxp3 in cell types other than Tregs. In this context, we evaluated the functions of Foxp3 in ovalbumin- and cockroach-induced asthma models. Foxp3-EGFP-expressing adenovirus or EGFP control adenovirus was administered intratracheally (i.t.), followed by challenge with ovalbumin (OVA) or cockroach extract to induce asthma. Th2 cytokine and immune cell profiles of bronchoalveolar lavage fluid (BALF), as well as serum IgE levels, were analyzed. Histological analyses were also conducted to demonstrate the effects of Foxp3 expression on airway remodeling, goblet cell hyperplasia and inflammatory responses in the lung. Adenoviral Foxp3 was expressed only in lung epithelial cells, and not in CD4+ or CD8+ cells. BALF from Foxp3 gene-delivered mice showed significantly reduced numbers of total immune cells, eosinophils, neutrophils, macrophages and lymphocytes in response to cockroach allergen or OVA. In addition, Foxp3 expression in the lung reduced the levels of Th2 cytokines and IgE in BALF and serum, respectively. Moreover, histopathological analysis also showed that Foxp3 expression substantially inhibited eosinophil infiltration into the airways, goblet cell hyperplasia and smooth muscle cell hypertrophy. Furthermore, when Tregs were depleted by diphtheria toxin in Foxp3DTR mice, the anti-asthmatic functions of Foxp3 were not altered in OVA-challenged asthma models. In this study, our results suggest that Foxp3 expression in lung epithelial cells, and not in Tregs, inhibited OVA- and cockroach extract-induced asthma.

Highlights

Mutation of the transcription factor Forkhead box P3 (Foxp3) leads to fatal autoimmune diseases in mice and humans.[1,2] Foxp[3] was initially shown to be a key transcription factor in the control of regulatory T-cell (Treg) function,[3] there are an increasing number of reports describing the functions of Foxp[3] in other cell types
Ad Foxp3-EGFP or Ad-EGFP are only expressed in lung epithelial cells To investigate which cell types were infected following intratracheal Ad Foxp3-EGFP or Ad-EGFP treatment, we analyzed the EGFP expression in lung tissue by confocal microscopy and flow cytometry
When we analyzed the single-cell suspensions from dissociated lungs after Ad Foxp3-EGFP or Ad-EGFP infection, Foxp[3] was expressed in CD326+ epithelial cells (Figure 1d), but not in CD4+ or CD8+ cells (Figures 1b and c). These results show that i.t. administered Ad Foxp3-EGFP and Ad-EGFP were only expressed in epithelial cells

Summary

Introduction

Mutation of the transcription factor Forkhead box P3 (Foxp3) leads to fatal autoimmune diseases in mice and humans.[1,2] Foxp[3] was initially shown to be a key transcription factor in the control of regulatory T-cell (Treg) function,[3] there are an increasing number of reports describing the functions of Foxp[3] in other cell types. Foxp[3] is known to be expressed in epithelial cells of many lineages, including breast.[4] In addition, by using Rag2−/− mice, Chen et al.,[4] showed that Foxp[3] is expressed in the airway epithelium. Foxp[3] expression represses the epidermal growth factor receptor (HER2/ErbB2) and SKP2 oncogenes in breast cancer cells.[5,6] we have previously studied the expression and functions of Foxp[3] in microglia.[7,8] In this context, in the present study, we examine the function of the Foxp[3] gene in asthma models

Methods

Results

Conclusion