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

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.

Day‐7 embryos generate an anti‐inflammatory immune response in peripheral blood immune cells in superovulated cows

“…There is another possibility that IFNT can reach to the uterine stroma, [26][27][28] in which immune cells such as dendritic cells (DCs) and macrophages are present in the uterus in cows. 35 In our study, Foxp3 expression was activated in peripheral blood PMNs by the presence of Day-7 embryos in the cow uterus. 30 Foxp3 is a key transcription factor that regulates the development and function of CD4+CD25+ regulatory T cells (Treg).…”

“…33 Recently, functions of Foxp3 were also reported in other cell types, specifically in epithelial cells of many lineages including the breast 34 and lungs. 35 In our study, Foxp3 expression was activated in peripheral blood PMNs by the presence of Day-7 embryos in the cow uterus.…”

Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis

“…It is reported that neutrophils firstly migrate to the lung in the early inflammation phase in the BLM-model [ 19 ]. Additionally, Park et al reported that forced expression of Foxp3 reduced airway inflammation in a mouse asthma model via inhibiting accumulation of total immune cells, eosinophils, neutrophils, macrophages and lymphocytes neutrophil accumulation in BALF [ 20 ]. Altogether, in early inflammation of BLM-induced fibrosis, Skp2 negatively regulates Treg via suppression of Foxp3 and p27/p21.…”

Adenovirus-mediated Gene Therapy for Allergy

“…A recent study demonstrated that Ad-expressed FOXP3 could exert anti-allergic effects independent of Treg cells, and was similarly effective for treating different allergen-induced lung injuries. 69 The third question concerns preexisting immunity (PEI). Antibodies against Ads are prevalent in the human population.…”

“…Recently, Park et al found that Admediated FOXP3 expression in lung epithelial cells can reduce airway inflammation in both OVA-induced and cockroach-induced asthma models. 69 The Notch signaling pathway mediates activation of NF-kB, 70 which is critical for GATA3 expression and Th2 differentiation. 71,72 KyoT2 is a negative modulator of Notch signaling.…”