Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA320713 | ENA |
REPOSITORIES: ENA
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Project description:Eosinophilic esophagitis (EoE) is a T helper type 2 (TH2) cytokine-associated disease charaterized by eosinophil infiltration, epithelial cell hyperplasia and tissue remodeling. Recent studies have highlighted a major contribution for IL-13 in EoE pathogenesis. Paired immunoglobulin-like receptor (PIR)-B is a cell surface immune-inhibitory receptor that is expressed by eosinophils and postulated to regulate eosinophil development and migration. We report that Pirb is upregulated in the esophagus after inducible overexpression of IL-13 (CC10-IL13 Tg mice) and is overexpressed by esophageal eosinophils. CC10-IL13Tg/PirB-/- mice displayed increased esophageal eosinophilia and EoE pahtology, including epithelial cell thickening, fibrosis and angiogenesis, compared with CC10-IL13 Tg/PirB+/+ mice. Transcriptome analysis of primary Pirb+/+ and Prib-/- esophageal eosinophils revealed increased expression of transcripts associated with promoting tissue remodeling in Pirb-/- eosinophils including pro-fibrotic genes, genes promoting epithelial-to-mesenchymal transition (EMT) and genes associated with epithelial growth. These data identify PIR-B as a molecular checkpoint in IL-13-induced eosinophil accumulation and activation, which may serve as a novel target for future therapy in EoE.
2016-05-05 | GSE81135 | GEO
Project description:Despite the well-recognized role of IL-13–induced transcriptional responses in allergic inflammation, the epigenetic mechanisms driven by IL-13 have not been well defined. We interrogated the transcriptional and epigenetic signatures of IL-13-induced epithelial responses focusing on the chromatin activation marks H3K4me3, H3K9Ac, and H3K27Ac. ChIP-sequencing analysis revealed that IL-13–inducible genes were epigenetically poised for induction and continued to accumulate epigenetic changes in response to IL-13. By intersecting the transcriptome and the epigenome of the IL-13 response, we identified neurotrophic tyrosine kinase receptor 1 (NTRK1) as a major target of IL-13 in epithelial cells. Using eosinophilic esophagitis as a model system for human allergic inflammation, we found that NTRK1 was dramatically induced in inflamed esophageal biopsies, and downstream mediators of NTRK1 signaling were elevated in diseased tissue. The NTRK1 ligand nerve growth factor (NGF) was constitutively expressed in control and disease states, indicating that induction of the receptor by IL-13 limited pathway activation. In epithelial cells, NGF and IL-13 synergistically induced transcription and secretion of the key eosinophil chemoattractant CCL26 (eotaxin-3). In summary, we demonstrate that IL-13–mediated allergic responses are epigenetically driven and identify NTRK1 as a novel epigenetic and transcriptional target of IL-13 that uniquely contributes to allergic inflammation. Human esophageal epithelial cell line TE-7 was stimulated with IL-13 at 100 ng/ml for 2 hr, 6 hr and 24 hr and subjected to RNA-sequencing. In parallel, TE-7 cells were induced with IL-13 for 6 hr and subjected to ChIP-sequencing analysis for H3K4me3, H3K9Ac and H3K27Ac activating chromatin marks.
2015-04-09 | E-GEOD-57637 | biostudies-arrayexpress
Project description:Eosinophils are major effector cells in type 2 inflammatory responses and become activated in response to IL-4 and IL-33, yet the molecular mechanism remains unclear. We examined the direct effect of these cytokines on eosinophils and demonstrated that murine eosinophils respond to IL-4 and IL-33 by phosphorylation of STAT-6 and NFkB, respectively. RNA sequencing analysis of murine eosinophils indicated that IL-33 regulates 519 genes, whereas IL-4 regulates only 28 genes, including 19 IL-33-regulated genes. Interestingly, IL-33 induced eosinophil activation via two distinct mechanisms, IL-4 independent and IL-4 secretion/auto-stimulation dependent. Anti-IL-4 or anti-IL-4Ra antibody-treated eosinophils, as well as Il4- or Stat6-deficient eosinophils, had attenuated protein secretion of a subset of IL-33-induced genes, including Retnla and Ccl17. However, the induction of most IL-33-regulated transcripts (e.g. Il6 and Il13) was IL-4 independent and blocked by NFkB inhibition. Indeed, IL-33 induced the rapid release of pre-formed IL-4 protein from eosinophils by an NFkB-dependent mechanism. Thus, we have identified a novel activation pathway in murine eosinophils that is induced by IL-33 and differentially dependent upon IL-4. These data suggest that IL-4 plays a critical role in auto-amplification of IL-33-induced eosinophil activation and could be a potential target for therapeutic approaches in IL-33-related eosinophil-associated diseases. Low density bone marrow derived murine eosinophils were generated in culture over the period of 14 days. Eosinophils were activated by either IL-33 or IL-4 at 10 ng/ml for 1hr and 4hr. RNA was collected and subjected to next generation sequencing.
2013-08-01 | E-GEOD-43660 | biostudies-arrayexpress
Project description:Despite the well-recognized role of IL-13–induced transcriptional responses in allergic inflammation, the epigenetic mechanisms driven by IL-13 have not been well defined. We interrogated the transcriptional and epigenetic signatures of IL-13-induced epithelial responses focusing on the chromatin activation marks H3K4me3, H3K9Ac, and H3K27Ac. ChIP-sequencing analysis revealed that IL-13–inducible genes were epigenetically poised for induction and continued to accumulate epigenetic changes in response to IL-13. By intersecting the transcriptome and the epigenome of the IL-13 response, we identified neurotrophic tyrosine kinase receptor 1 (NTRK1) as a major target of IL-13 in epithelial cells. Using eosinophilic esophagitis as a model system for human allergic inflammation, we found that NTRK1 was dramatically induced in inflamed esophageal biopsies, and downstream mediators of NTRK1 signaling were elevated in diseased tissue. The NTRK1 ligand nerve growth factor (NGF) was constitutively expressed in control and disease states, indicating that induction of the receptor by IL-13 limited pathway activation. In epithelial cells, NGF and IL-13 synergistically induced transcription and secretion of the key eosinophil chemoattractant CCL26 (eotaxin-3). In summary, we demonstrate that IL-13–mediated allergic responses are epigenetically driven and identify NTRK1 as a novel epigenetic and transcriptional target of IL-13 that uniquely contributes to allergic inflammation.
2015-04-09 | GSE57637 | GEO
Project description:Distinct subsets of eosinophils are reported in inflammatory and healthy tissues, yet the functions of uniquely specialized eosinophils and the signals that elicit them, particularly in eosinophilic esophagitis (EoE), are not well understood. Herein, we report an ex-vivo system wherein freshly isolated human eosinophils were cocultured with esophageal epithelial cells and disease-relevant pro-inflammatory (IL-13) or pro-fibrotic (TGF-β) cytokines. Our results demonstrate that disease-relevant pro-inflammatory and pro-fibrotic signals present in the esophagus of EoE patients cause distinct profiles of eosinophil activation and gene expression.
2024-11-06 | GSE264591 | GEO
Project description:Eosinophils are major effector cells in type 2 inflammatory responses and become activated in response to IL-4 and IL-33, yet the molecular mechanism remains unclear. We examined the direct effect of these cytokines on eosinophils and demonstrated that murine eosinophils respond to IL-4 and IL-33 by phosphorylation of STAT-6 and NFkB, respectively. RNA sequencing analysis of murine eosinophils indicated that IL-33 regulates 519 genes, whereas IL-4 regulates only 28 genes, including 19 IL-33-regulated genes. Interestingly, IL-33 induced eosinophil activation via two distinct mechanisms, IL-4 independent and IL-4 secretion/auto-stimulation dependent. Anti-IL-4 or anti-IL-4Ra antibody-treated eosinophils, as well as Il4- or Stat6-deficient eosinophils, had attenuated protein secretion of a subset of IL-33-induced genes, including Retnla and Ccl17. However, the induction of most IL-33-regulated transcripts (e.g. Il6 and Il13) was IL-4 independent and blocked by NFkB inhibition. Indeed, IL-33 induced the rapid release of pre-formed IL-4 protein from eosinophils by an NFkB-dependent mechanism. Thus, we have identified a novel activation pathway in murine eosinophils that is induced by IL-33 and differentially dependent upon IL-4. These data suggest that IL-4 plays a critical role in auto-amplification of IL-33-induced eosinophil activation and could be a potential target for therapeutic approaches in IL-33-related eosinophil-associated diseases.
2013-08-01 | GSE43660 | GEO
Project description:Eosinophilic esophagitis (EoE) is a chronic immune-mediated disorder triggered by specific food antigens, characterized by eosinophil-rich multicellular inflammation and structural changes in the epithelium. Treatment options for EoE include dietary therapy, pharmacological therapy, or a combination of both, chosen based on the patient's preference and clinical progression. Pharmacological options include proton pump inhibitors (PPIs), corticosteroids, and biologic therapy. Although PPI therapy is used for EoE management, its underlying mechanism of action remains unclear. To investigate the effects of omeprazole, an orally bioavailable PPI commonly used for EoE therapy, on the dynamics of esophageal epithelial barrier function and inflammation, we employed air-liquid interface (ALI) culture. We examined how omeprazole affects gene expression changes caused by IL-13 treatment. ALI cultures were treated with 100 ng/ml of IL-13 and/or 50 µM of acid-activated omeprazole for 96 hours, and bulk RNA sequencing was performed to analyze the epithelial-specific transcriptomes of IL-13 and/or omeprazole-treated ALI. Our findings suggest potential gene interactions where omeprazole may mitigate transcriptional changes induced by IL-13, indicating that omeprazole may attenuate IL-13 mediated epithelial dysfunction relevant to EoE pathophysiology by modulating pathways associated with inflammation, tissue repair, and cell-cell communication.
2024-09-13 | GSE273039 | GEO
Project description:3 eosinophilic esophagitis biopsies, cultured and stimulated with IL-13 : each of them was either left unstimulated or stimulated (100ng for 48h) We used microarray to uncover the IL-13-induced genes in esophageal epithelial cells of the esophagus Keywords: treated vs non treated
2007-12-21 | GSE8853 | GEO
Project description:Background: Dupilumab, a fully human monoclonal antibody that binds IL-4Ra and inhibits signaling of both IL-4 and IL-13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL-4 and IL-13 in type 2 inflammation and report dupilumab mechanisms of action. Methods: Using primary cell assays and a mouse model of house dust mite induced asthma, we compared IL-4 versus IL-13 versus IL-4Ra blockers. Results: Intranasal administration of either IL-4 or IL-13 confers an asthma-like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head to head studies, either IL-4 or IL-13 inhibition to dual IL-4/IL-13 inhibition, we demonstrate that blockade of both IL-4 and IL-13 is required to broadly block type 2 inflammation, which translates to protection from allergen-induced lung function impairment. Notably, only dual IL-4/IL-13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils contribute to disease pathology. Conclusions: Overall, these data support IL-4 and IL-13 as key drivers of type 2 inflammation, and help provide insight into the therapeutic mechanism of dupilumab, a dual IL-4/IL-13 blocker, in multiple type 2 diseases.
2019-11-25 | GSE140900 | GEO
Project description:3 eosinophilic esophagitis biopsies, cultured and stimulated with IL-13 : each of them was either left unstimulated or stimulated (100ng for 48h); We used microarray to uncover the IL-13-induced genes in esophageal epithelial cells of the esophagus Experiment Overall Design: 3 biopsies from EE patients were obtained and primary epithelial cell were cultured and either left unstimulated or stimulated with IL-13 followed by RNA extraction and hybridization on Affymetrix microarrays.
2008-06-20 | E-GEOD-8853 | biostudies-arrayexpress