RNAseq analysis of mouse lung transcriptome from allergic and non-allergic mice prior to and following lung Klebsiella pneumoniae infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE57602 | GEO | 2014/07/14
SECONDARY ACCESSION(S): PRJNA246779
REPOSITORIES: GEO
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Project description:Allergic airway inflammation is a chronic inflammatory condition resulting from uncontrolled immune responses to environmental antigens. While it is well-established that allergic immune responses exhibit a high degree of diversity, driven by primary effector cell types like eosinophils, neutrophils, or CD4 T cells with distinct effector signatures, the exact mechanisms responsible for such pathogenesis remain largely elusive. Foxp3+ regulatory T cells (Treg) is an indispensable immune regulator during chronic inflammation including allergic airway inflammation. Emerging evidence suggests that Tregs infiltrating inflamed tissues exhibit distinct phenotypes dependent on the specific tissue sites and can display significant heterogeneity and tissue residency. Whether diverse allergic inflammatory responses in the lung influences infiltrating Treg heterogeneity or Treg lung residency has not previously been explored. We employed an unbiased single-cell RNAseq approach to study lung-infiltrating Tregs in models of eosinophilic and neutrophilic airway inflammation models, in which Tregs are critical immune regulators of inflammation. We found that lung-infiltrating Tregs are highly heterogeneous and that Tregs displaying lung residency phenotypes are significantly different depending on the types of inflammation. Tregs expression of ST2, a receptor for alarmin cytokine IL-33, was predominantly induced by eosinophilic inflammation and by tissue residency. However, Treg-specific ST2 deficiency did not affect the development of eosinophilic allergic inflammation nor the generation of lung resident Tregs. These results uncover a striking heterogeneity among Tregs infiltrating the lungs during allergic airway inflammation. The results also indicate that varying types of inflammation may give rise to phenotypically distinct lung resident Tregs. Thus, the present study underscores a novel mechanism by which inflammatory environments may shape the composition of infiltrating Tregs, allowing them to regulate inflammatory responses through tissue-adapted mechanisms.
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Project description:Introduction: Prenatal and postnatal cigarette smoke exposure enhances the risk of developing asthma. Despite this as well as other smoking related risks, 11% of women still smoke during pregnancy. We hypothesized that cigarette smoke exposure during prenatal development generates long lasting differential methylation altering transcriptional activity that correlates with disease. Methods: In a house dust mite (HDM) model of allergic airway disease, we measured airway hyperresponsiveness (AHR) and airway inflammation between mice exposed prenatally to cigarette smoke (CS) or filtered air (FA). DNA methylation and gene expression were then measured in lung tissue. Results: We demonstrate that HDM-treated CS mice develop a more severe allergic airway disease compared to HDM-treated FA mice including increased AHR and airway inflammation. While DNA methylation changes between the two HDM-treated groups failed to reach genome-wide significance, 99 DMRs had an uncorrected p-value < 0.001. 6 of these 99 DMRs were selected for validation, based on the immune function of adjacent genes, and only 2 of the 6 DMRs confirmed the bisulfite sequencing data. Additionally, genes near these 6 DMRs (Lif, Il27ra, Tle4, Ptk7, Nfatc2, and Runx3) are differentially expressed between HDM-treated CS mice and HDM-treated FA mice. Conclusions: Our findings confirm that prenatal exposure to cigarette smoke is sufficient to modify allergic airway disease, however, it is unlikely that specific methylation changes account for the exposure-response relationship. These findings highlight the important role in utero cigarette smoke exposure plays in the development of allergic airway disease. Lung DNA methylation profiles of mice exposed in utero to cigarette smoke (CS) then treated with house dust mite (HDM, n = 8) or saline (n = 6), or exposed in utero to filtered air (FA) then treated with HDM (n = 9) or saline (n = 6)
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Project description:Asthma is a common chronic inflammatory airway condition with a strong genetic and inheritability component, as siblings and first-degree relatives of those with the disease are often affected. For our studies, we used a well-characterized transgenic mouse model of allergic airway inflammation induced by IL13. In this model, IL13 is conditionally overexpressed in the mouse lung when treated with doxycycline. Upon IL13 induction, these mice showed inflammatory cell infiltration, pronounced emphysema, increased pulmonary compliance, lung volume enlargement, mucus metaplasia, and increased expression of matrix metalloproteinases and cathepsins in the lung. We performed gene expression microarray to examine the changes in gene expression during IL13-induced allergic airway inflammation. The CC10-rtTA-IL13 transgenic (TG) and wildtype (WT) mice were treated with doxycycline for seven days. Mice were euthanized and the left upper lobes from all mice were removed for RNA extraction using the TRIzol method.
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Project description:Epigenetic changes have been implicated in pathogenesis of asthma. We sought to determine if IL13, a key cytokine in airway inflammation and remodeling, induced epigenetic DNA methylation changes in the airways in conjunction with its transcriptional gene regulation. For our studies, we used a well-characterized transgenic mouse model of allergic airway inflammation induced by IL13. In this model, IL13 is conditionally overexpressed in the mouse lung when treated with doxycycline. Upon IL13 induction, these mice showed inflammatory cell infiltration, pronounced emphysema, increased pulmonary compliance, lung volume enlargement, mucus metaplasia, and increased expression of matrix metalloproteinases and cathepsins in the lung. We performed MeDIP microarray to examine the changes in DNA promoter methylation during IL13-induced allergic airway inflammation. The CC10-rtTA-IL13 transgenic (TG) and wildtype (WT) mice were treated with doxycycline for seven days. Mice were euthanized and the left lower lobes from all mice were removed for DNA extraction followed by MeDIP array analysis.
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Project description:This SuperSeries is composed of the following subset Series: GSE35979: Gene expression data from IL13-induced allergic airway inflammation of mice lungs GSE35980: MicroRNA expression data from IL13-induced allergic airway inflammation of mice lungs GSE37079: Methylated DNA immunoprecipitation (MeDIP) microarray data from IL13-induced allergic airway inflammation of mouse lungs Refer to individual Series
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Project description:Asthma is a common chronic inflammatory airway condition with a strong genetic and inheritability component, as siblings and first-degree relatives of those with the disease are often affected. For our studies, we used a well-characterized transgenic mouse model of allergic airway inflammation induced by IL13. In this model, IL13 is conditionally overexpressed in the mouse lung when treated with doxycycline. Upon IL13 induction, these mice showed inflammatory cell infiltration, pronounced emphysema, increased pulmonary compliance, lung volume enlargement, mucus metaplasia, and increased expression of matrix metalloproteinases and cathepsins in the lung. We performed gene expression microarray to examine the changes in gene expression during IL13-induced allergic airway inflammation.
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Project description:Epigenetic changes have been implicated in pathogenesis of asthma. We sought to determine if IL13, a key cytokine in airway inflammation and remodeling, induced epigenetic DNA methylation changes in the airways in conjunction with its transcriptional gene regulation. For our studies, we used a well-characterized transgenic mouse model of allergic airway inflammation induced by IL13. In this model, IL13 is conditionally overexpressed in the mouse lung when treated with doxycycline. Upon IL13 induction, these mice showed inflammatory cell infiltration, pronounced emphysema, increased pulmonary compliance, lung volume enlargement, mucus metaplasia, and increased expression of matrix metalloproteinases and cathepsins in the lung. We performed MeDIP microarray to examine the changes in DNA promoter methylation during IL13-induced allergic airway inflammation.
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