17-beta estradiol protects esophageal epithelium from IL-13-induced barrier dysfunction and remodeling
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE119239 | GEO | 2019/08/30
REPOSITORIES: GEO
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Project description:BackgroundThe incidence of eosinophilic esophagitis (EoE) is greater in male than female subjects, and the underlying molecular basis for this sex bias remains unclear.ObjectiveWe sought to delineate the contribution of the sex hormone estrogen to the EoE phenotype and esophageal epithelial barrier function and remodeling.MethodsWe performed demographic and incidence analyses of EoE in male and female subjects from a single-center pediatric cohort. Estrogen-responsive gene expression analyses and estrogen receptor (ESR) immunofluorescence staining of esophageal biopsy specimens from patients with EoE and control subjects were performed. The effect of 17β-estradiol (E2) on IL-13-induced signaling pathways, gene expression, and esophageal epithelial architecture and barrier function in a primary human esophageal keratinocyte cell (EPC2) culture system (EPC2-air-liquid interface) was examined.ResultsWe observed a male predominance in patients with EoE. Analyses of RNA sequencing data sets revealed a significant dysregulation of the estrogen-responsive gene network and expression of ESR1 and ESR2 in esophageal biopsy specimens from patients with EoE compared with control subjects. IL-13 stimulation of EPC2-air-liquid interface cells led to altered cellular architecture with induced dilation of intercellular spaces and barrier dysfunction. Pretreatment of EPC2s with E2 prior to IL-13 exposure abrogated IL-13-induced architectural changes and esophageal barrier dysfunction. Mechanistically, E2-protective effects were dependent on ESR2 and associated with diminishing of IL-13-induced tyrosine kinase 2 and signal transducer and activator of transcription 6 phosphorylation and EoE-dysregulated gene expression.ConclusionsEstrogen-responsive genes are modified in patients with EoE compared with control subjects. E2 attenuated IL-13-induced architectural changes and esophageal epithelial barrier dysfunction through inhibition of the IL-13/tyrosine kinase 2/signal transducer and activator of transcription 6 pathway via ESR2-dependent process. Estrogen hormone signaling may protect against development of EoE in female subjects.
| S-EPMC6556402 | biostudies-literature
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:Patients with Eosinophilic esophagitis (EoE) require long-lasting resolution of inflammation to prevent fibrostenosis and dysphagia. However, the dissociation between symptoms and histologic improvement suggests persistent molecular drivers despite remission. We aimed to characterize persisting molecular alterations in pediatric patients with EoE using tissue proteomics. Esophageal tissue biopsies (n=151) and clinical data were collected prospectively from pediatric patients with EoE (N=34), gastroesophageal reflux disease (GERD; N=10; inflammatory controls) or functional disorders (FD; N=20; non-inflammatory controls). Biospies (n=131) acquired from the diagnostic endoscopy and up to 7 follow-ups were considered for proteome analysis in patients with EoE, while for GERD and FD only biopsies from initial diagnosis were included. Histologically active EoE (15 eosinophils per high power field (hpf)) was diagnosed in 79 biopsies and 52 samples derived from patients with EoE in remission (15 eosinophils per hpf). After microdissection of the epithelium proteins were extracted from the esophageal tissue followed by a liquid chromatography-tandem mass spectrometry. Proteomic analysis identified 3,704 different proteins in total across all samples.
2024-09-23 | PXD052250 | Pride
Project description:This study sought to evaluate the diffferential gene expression of human Eosinophilic Esophagitis (EoE) patients compared to control patients. Abstract from associated publication: Eosinophilic Esophagitis (EoE) is a chronic allergic disease characterized by progressive inflammation of the esophageal mucosa. While the transcriptome of EoE has been reported, few studies have examined the genetics among both adult and pediatric EoE populations. Here, we use microarray analysis to interrogate gene expression using esophageal biopsies from EoE and Control subjects with a wide age distribution. Analysis of differential gene expression and prediction of impaired pathways was compared using conventional transcriptome analysis programs and an artificial intelligence-based ADVAITA program. Principal Components Analysis revealed samples cluster by disease status (EoE and Control) irrespective of clinical features like sex, age, and disease severity. Global transcriptomic analysis revealed differential expression of several genes previously reported in EoE (CCL26, CPA3, POSTN, CTSC, ANO1, CRISP3, SPINK7). In addition, we identified differential expression of several genes from the MUC and SPRR families, which has not been previously reported. Our findings suggest their involvement in impaired barrier integrity and loss of epidermal cell differentiation in EoE patients. These findings present two new gene families that are differentially expressed in EoE patients in both adult and pediatric populations, which presents an opportunity for a future therapeutic targets that would be useful in a large demographic of patients.
2023-08-10 | GSE228083 | GEO
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:Eosinophilic esophagitis (EoE) is a chronic, allergic inflammatory disease of the esophageal mucosa. Although type 2 cytokines are predominant, targeting type 2 inflammation alone is not always effective for all patients. In EoE patients, the transcriptional profiling of esophageal biopsy reveals upregulation of type I and II interferon (IFN) response, dysregulated immune signaling, and downregulation of esophageal-specific genes. However, further investigation is needed to examine the gene expression changes in esophageal epithelium because it plays an important role in EoE. To investigate the upregulation of Interferon Stimulated Genes (ISGs) in EoE esophageal epithelium, we isolated epithelial cells from active EoE patients and non-EoE controls. We performed bulk RNA sequencing to analyze the epithelial-specific transcriptome in EoE. Unsupervised hierarchical clustering of the most variable genes differentiated the active EoE biopsies from non-EoE controls. Gene set enrichment analysis identified IFN-γ response as the most significant upregulated pathway.
2024-02-26 | GSE234973 | GEO
Project description:Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus featuring increased esophageal interleukin-13 (IL-13) levels and impaired barrier function. Herein, we investigated leucine-rich repeat-containing protein 31 (LRRC31) in human EoE esophageal tissue and IL-13-treated esophageal epithelial cells. LRRC31 had basal mRNA expression in colonic and airway mucosal epithelium. Esophageal LRRC31 mRNA and protein increased in active EoE and strongly correlated with esophageal eosinophilia and IL13 and CCL26 (chemokine (C-C motif) ligand 26) mRNA expression. IL-13 treatment increased LRRC31 mRNA and protein in air-liquid interface-differentiated esophageal epithelial cells (EPC2s). At baseline, differentiated LRRC31-overexpressing EPC2s had increased barrier function (1.9-fold increase in transepithelial electrical resistance (P<0.05) and 2.8-fold decrease in paracellular flux (P<0.05)). RNA sequencing analysis of differentiated LRRC31-overexpressing EPC2s identified 38 dysregulated genes (P<0.05), including five kallikrein (KLK) serine proteases. Notably, differentiated LRRC31-overexpressing EPC2s had decreased KLK expression and activity, whereas IL-13-treated, differentiated LRRC31 gene-silenced EPC2s had increased KLK expression and suprabasal epithelial detachment. We identified similarly dysregulated KLK expression in the esophagus of patients with active EoE and in IL-13-treated esophageal epithelial cells. We propose that LRRC31 is induced by IL-13 and modulates epithelial barrier function, potentially through KLK regulation.
| S-EPMC4833724 | biostudies-other
Project description:To investigate gene expression signature of the human esophageal epithelium at the homeostatic and inflammatory conditions we performed scRNAseq on the human esophageal biopsies obtained from the healhy patients, patients with active eosinophilic esophagitis (EoE) and patients in the remission.
2022-06-15 | GSE201153 | GEO
Project description:Estrogen replacement therapy increases the risk of human ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. This study uses primary cultures of mouse ovarian surface epithelium (OSE) to demonstrate that one possible mechanism by which estrogen accelerates the initiation of ovarian cancer is by up-regulation of microRNA-378 via the ESR1 pathway to result in the down-regulation of a tumour suppressor called Disabled-2 (Dab2). Estrogen suppression of Dab2 was reproducible in vivo and across many cell types including mouse oviductal epithelium and primary cultures of human ovarian cancer cells. Suppression of Dab2 resulted in increased proliferation, loss of contact inhibition, morphological dysplasia, and resistance to oncogene-induced senescence - all factors that can sensitize OSE to transformation. Given that DAB2 is highly expressed in healthy human OSE and is absent in the majority of ovarian tumours, this study has taken the first steps to provide a mechanistic explanation for how estrogen therapy may play a role in the initiation of ovarian cancer.
| S-EPMC5711839 | biostudies-literature
Project description:Analysis of steady-state mRNA levels in 27 samples from healthy controls and patients with fibrostenotic EoE and non-fibrostenotic EoE. Participants range 5 – 18 years old. EoE participants had >15 eosinophils per hpf (eos/hpf) and were classified as fibrostenotic (FS) or non-fibrostenotic (non-fs). FS EoE: having either a) a stricture and/or b) grade 2 or 3 concentric esophageal rings and an esophageal distensibility < 15 mm. Non-fs EoE: no clinical evidence for stricture, circumferential rings or history of food impaction. Included control subjects had no identified abnormalities on endoscopy or histology. Results provide insight into the pathways involved in fibrostenotic remodeling in EoE.
2023-04-08 | GSE197702 | GEO