Unknown,Transcriptomics,Genomics,Proteomics

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Distinct roles of FOXA2 and FOXA3 in allergic airway disease

ABSTRACT: Allergen challenge induced mucus metaplasia modify the expression of two transcription factors belonging to the FOXA family: FOXA2 and FOXA3. Foxa2 expression is decreased during allergic airway disease whereas, Foxa3 expression is increased by allergen. Therefore, we asked whether persistent expression of Foxa2 prevents mucus and whether absence of Foxa3 affects mucus or other features asociated with allergic airway disease. We analyzed the effects of these changes in FOXA transcription factor expression using Foxa2 transgenic mice and Foxa3-/- mice. We found that persistent expression of FOXA2 reduced mucus but the absence of FOXA3 had no effect on mucus production induced by allergen challenge. However, the absence of FOXA3 decreased airway hyperreactivity and increased IgE production and eosinophilic inflammation but none of these features were affected by persistent expression of FOXA2. These results indicate that FOXA3 has functions distinct from those of FOXA2 in the allergic response. Keywords: gene expression comparison between Foxa3-/- and littermate control mice both challenged with OVA DNA miocroarrays were used to analyze lung mRNA expression of Foxa3 KO and littermate control mice challenged with saline or OVA. The experiment incorporated a 1 color design and used Agilent arrays that contained roughly 44,000 60mer probes that provide complete coverage of the mouse genome. 11 arrays were hybridized and represent 3 lung samples for groups WT saline, WT OVA and KO OVA. There are 2 lung samples for the KO saline group.

ORGANISM(S): Mus musculus

SUBMITTER: Sung-Woo Park

PROVIDER: E-GEOD-13382 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Studying the proteomes of tissue-derived extracellular vesicles (EVs) can lead to the identifica-tion of biomarkers of disease and can provide a better understanding of cell-to-cell communica-tion in both healthy and diseased tissue. The aim of this study was to apply our previously es-tablished tissue-derived EV isolation protocol to mouse lungs in order to determine the changes in the proteomes of lung tissue-derived EVs during allergen-induced eosinophilic airway in-flammation. A mouse model for allergic airway inflammation was used by sensitizing the mice intraperitoneal with ovalbumin (OVA), and one week after the final sensitization, the mice were challenged intranasal with OVA or PBS. The animals were sacrificed 24 h after the final chal-lenge, and their lungs were removed and sliced into smaller pieces that were incubated in cul-ture media with DNase I and Collagenase D for 30 min at 37 °C. Vesicles were isolated from the medium by ultracentrifugation and bottom-loaded iodixanol density cushions, and the proteo-mes were determined using quantitative mass spectrometry. More EVs were present in the lungs of the OVA-challenged mice compared to the PBS-challenged control mice. In total, 4510 proteins were quantified in all samples. Among them, over 1000 proteins were significantly altered (fold change >2), with 614 proteins being increased and 425 proteins being decreased in the EVs from OVA-challenged mice compared to EVs from PBS-challenged animals. The associated cellular components and biological processes were analyzed for the altered EV proteins, and the proteins enriched during allergen-induced airway inflammation were mainly associated with gene on-tology (GO) terms related to immune responses. In conclusion, EVs can be isolated from mouse lung tissue, and the EVs’ proteomes undergo changes in response to allergen-induced airway in-flammation. This suggests that the composition of lung-derived EVs is altered in diseases asso-ciated with inflammation of the lung, which may have implications in type-2 driven eosino-philic asthma pathogenesis.

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Distinct roles of FOXA2 and FOXA3 in allergic airway disease

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