IL-13 stimulation of primary human bronchial epithelial cells in control individuals and patients with asthma.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE206510 | GEO | 2023/01/30
REPOSITORIES: GEO
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Project description:High numbers of goblet cells in airways contribute to the mucus obstruction characteristic of asthmatic airways. Allergen challenged mice exhibit robust expression of goblet cells within airway surface epithelium. This study looks at the temporal analysis of IL-13 exposed murine airways to elucidate pathways that result in differentiation of airway epithelial cells to goblet cells.
2008-06-13 | E-GEOD-481 | biostudies-arrayexpress
Project description:BACKGROUND: The type 2 cytokine-high asthma endotype (T2H) is characterized by IL-13-driven mucus obstruction of the airways. To investigate this poorly understood pathobiology, we characterized IL-13 effects on human airway epithelial cultures using single cell RNA-sequencing, finding that IL-13 generated a novel transcriptional state for each cell type. Specifically, we discovered a mucus secretory program induced by IL-13 in all cell types which converted both mucus and defense secretory cells into a metaplastic state with emergent mucin production and secretion, while leading to ER stress and cell death in ciliated cells. The IL-13-remodeled epithelium secreted a pathologic, mucin-imbalanced, and innate immunity-depleted proteome that arrested mucociliary motion. Signatures of IL-13-induced cellular remodeling were mirrored by transcriptional signatures characteristic of the nasal airway epithelium within T2H versus T2-low asthmatic children. Our results reveal the epithelium-wide scope of T2H asthma and present novel therapeutic targets for restoring normal epithelial function.
2020-07-13 | GSE145013 | GEO
Project description:High numbers of goblet cells in airways contribute to the mucus obstruction characteristic of asthmatic airways. Allergen challenged mice exhibit robust expression of goblet cells within airway surface epithelium. This study looks at the temporal analysis of IL-13 exposed murine airways to elucidate pathways that result in differentiation of airway epithelial cells to goblet cells. Keywords: other
2003-07-16 | GSE481 | GEO
Project description:Purpose: Build genesets using text mining and validate the geneset with data from public repository and a dataset generated in house using in vitro models and RNA-seq Methods: Mucus hypersecretion and mucociliary dysfucntion adverse outcome pathways (AOPs) genesets were build using the text mining method described by Rani et al., 2015. Validation was performed using RNA expression data from cigarette and e-cigarette aerosol treated cells, IL-13 treated airway cells, and COPD-lung biopsies. The cigarette and e-cigarette aerosol RNA-samples from airway cells were generated and sequenced in house. The other dataset were publically available. Results: Using unsupervised clustering, the mucus hypersecretion and mucociliary dysfunction genesets were able to discriminate the cigartte treated cells from the e-cigarettes and the air control. The e-cigarette and the air control clustered together. Clustering was also observed with IL-13 treated cells. IL-13 is an induced of mucus hypersecretion. Clustering was not observed when COPD RNA-seq samples were used. PCA analysis revealed some degree of grouping based on disease status, but this was also heavily confounded by other parameters. Conclusions: Our study described the first application of text mining to build genesets relevant to AOPs. In vitro validation confirmed the genesets could discriminates between treatment that induce mucus hypersecretion phenotypes, however this could not be confirmed with COPD biopsy samples. This could be due to a series of technical confouding factors and the heterogeneity of the COPD disease.
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Project description:Goblet cell hyperplasia (GCH) is a feature of respiratory diseases characterized by mucus hypersecretion. GCH is driven by Th2 cytokines such as IL-4. To investigate the gene expression changes associated with GCH, we treated human bronchial epithelial cells with IL-4. By microarray analysis and functional studies, we found that IL-4 promotes a profound change that results in enhanced bicarbonate secretion. This change may be required to support mucus release.
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Project description:Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of airway obstruction, hyperresponsiveness, remodeling, and eosinophilia. Phospholipase A2s (PLA2s), which release fatty acids and lysophospholipids from membrane phospholipids, have been implicated in exacerbating asthma by generating pro-asthmatic lipid mediators, but an understanding of the association between individual PLA2 subtypes and asthma is still incomplete. Here, we show that group III secreted PLA2 (sPLA2-III) plays an ameliorating, rather than aggravating, role in asthma pathology. In both mouse and human lungs, sPLA2-III was expressed in bronchial epithelial cells and decreased during the asthmatic response. In an ovalbumin (OVA)-induced asthma model, Pla2g3 knockout (-/-) mice exhibited enhanced airway hyperresponsiveness, eosinophilia, OVA-specific IgE production, and type 2 cytokine expression as compared to Pla2g3 wild-type (+/+) mice. Lipidomics analysis showed that the pulmonary levels of several lysophospholipids, including lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidic acid (LPA), were decreased in OVA-challenged Pla2g3-/- mice relative to Pla2g3+/+ mice. LPA receptor 2 agonists suppressed thymic stromal lymphopoietin expression in bronchial epithelial cells and reversed airway hyperresponsiveness and eosinophilia in Pla2g3-/- mice, suggesting that sPLA2-III negatively regulates allergen-induced asthma at least by producing LPA. Thus, the activation of the sPLA2-III-LPA pathway may be a new therapeutic target for allergic asthma. Microarray gene profiling of the bronchial epithelial cells isolated from OVA-challenged lung revealed the increased expression of various chemokines and type 2 epithelial cytokines in bronchial epithelial cells from Pla2g3-/- mice as compared to those from Pla2g3+/+ mice following OVA challenge.
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Project description:By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that ITLN1 gene expression is significantly reduced and ITLN-1 protein expression is lost through a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies one of the first biomarkers and targetable pathways for the treatment of mucus obstruction in asthma.
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Project description:Primary culture airway epithelial cells, grown under physiologic air-liquid interface conditions, with, or without IL-13 in order to study the effects of this cytokine on mucous cell metaplasia, an important feature of asthma and COPD. Keywords: IL13, mucus, goblet cell RNA was isolated from primary culture airway epithelial cells grown at air-liquid interface, treated with or without IL-13 for 21 days.
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Project description:Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of airway obstruction, hyperresponsiveness, remodeling, and eosinophilia. Phospholipase A2s (PLA2s), which release fatty acids and lysophospholipids from membrane phospholipids, have been implicated in exacerbating asthma by generating pro-asthmatic lipid mediators, but an understanding of the association between individual PLA2 subtypes and asthma is still incomplete. Here, we show that group III secreted PLA2 (sPLA2-III) plays an ameliorating, rather than aggravating, role in asthma pathology. In both mouse and human lungs, sPLA2-III was expressed in bronchial epithelial cells and decreased during the asthmatic response. In an ovalbumin (OVA)-induced asthma model, Pla2g3-/- mice exhibited enhanced airway hyperresponsiveness, eosinophilia, OVA-specific IgE production, and type 2 cytokine expression as compared to Pla2g3+/+ mice. Lipidomics analysis showed that the pulmonary levels of several lysophospholipids, including lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidic acid (LPA), were decreased in OVA-challenged Pla2g3-/- mice relative to Pla2g3+/+ mice. LPA receptor 2 agonists suppressed thymic stromal lymphopoietin expression in bronchial epithelial cells and reversed airway hyperresponsiveness and eosinophilia in Pla2g3-/- mice, suggesting that sPLA2-III negatively regulates allergen-induced asthma at least by producing LPA. Thus, the activation of the sPLA2-III-LPA pathway may be a new therapeutic target for allergic asthma. Microarray gene profiling of the OVA-challenged lung revealed that the genes related to cytokines and inflammatory response were highly changed in Pla2g3-/- mice relative to Pla2g3+/+ mice
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Project description:Nociceptor neurons play a crucial role in maintaining the body’s homeostasis by detecting and responding to potential dangers in the environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors can contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance, in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we aimed to investigate the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identified a unique class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. In the ovalbumin mouse model of airway inflammation, these neurons undergo significant reprogramming characterized by the upregulation of the NPY receptor Npy1r. A screening of cytokines and neurotrophins revealed that IL-1β, IL-13 and BDNF drive part of this reprogramming. IL-13 triggered Npy1r overexpression in nociceptors via the JAK/STAT6 pathway. In parallel, sympathetic neurons and macrophages release NPY in the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. Single-cell RNA sequencing of lung immune cells has revealed that a cell-specific knockout of Npy1r in nociceptor neurons in asthmatic mice leads to an increase in airway inflammation mediated by T cells. Opposite findings were observed in asthmatic mice in which nociceptor neurons were chemically ablated. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, while a compensatory mechanism involving NPY1R limits nociceptor neurons’ activity.
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