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Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-?.

ABSTRACT: BACKGROUND:Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE. OBJECTIVE:We investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE. METHODS:LOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patients with EoE; cytokine-stimulated esophageal 3-dimensional organoids; and fibroblast-epithelial cell coculture, the latter coupled with fluorescence-activated cell sorting. RESULTS:Gene ontology and pathway analyses linked TNF-? and LOX expression in patients with EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNF-?-mediated epithelial LOX upregulation was recapitulated in 3-dimensional organoids and coculture experiments. We find that fibroblast-derived TNF-? stimulates epithelial LOX expression through activation of nuclear factor ?B and TGF-?-mediated signaling. In patients receiver operating characteristic analyses suggested that LOX upregulation indicates disease complications and fibrostenotic conditions in patients with EoE. CONCLUSIONS:There is a novel positive feedback mechanism in epithelial LOX induction through fibroblast-derived TNF-? secretion. Esophageal epithelial LOX might have a role in the development of fibrosis with substantial translational implications.

SUBMITTER: Kasagi Y

PROVIDER: S-EPMC6586527 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α.

Kasagi Yuta Y Dods Kara K Wang Joshua X JX Chandramouleeswaran Prasanna M PM Benitez Alain J AJ Gambanga Fiona F Kluger Jonathan J Ashorobi Tokunbo T Gross Jonathan J Tobias John W JW Klein-Szanto Andres J AJ Spergel Jonathan M JM Cianferoni Antonella A Falk Gary W GW Whelan Kelly A KA Nakagawa Hiroshi H Muir Amanda B AB

The Journal of allergy and clinical immunology 20181220 1

<h4>Background</h4>Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE.<h4>Objective</h4>We investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE.<h4>Methods</h4>LOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patie ...[more]

PMID: 30578874

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Project description:Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory disease of the esophagus characterized predominantly by eosinophilic inflammation, leading to esophageal dysfunction. Converging data have placed the esophageal epithelium at the center of disease pathogenesis. In particular, the main EoE disease susceptibility loci at 2p23 and 5p22 encode for gene products that are produced by the esophageal epithelium: the intracellular protease calpain 14 and thymic stromal lymphopoietin, respectively. Furthermore, genetic and functional data establish a primary role for impaired epithelial barrier function in disease susceptibility and pathoetiology. Additionally, the EoE transcriptome, a set of genes dysregulated in the esophagi of patients with EoE, is enriched in genes that encode for proteins involved in esophageal epithelial cell differentiation. This transcriptome has a high proportion of esophagus-specific epithelial genes that are notable for the unexpected enrichment in genes encoding for proteases and protease inhibitors, as well as in IL-1 family genes, demonstrating a previously unappreciated role for innate immunity responses in the esophagus under homeostatic conditions. Among these pathways, basal production of the serine protease inhibitor, Kazal-type 7 (SPINK7) has been demonstrated to be part of the normal differentiation program of esophageal epithelium. Profound lost expression of SPINK7 occurs in patients with EoE and is sufficient for unleashing increased proteolytic activity (including urokinase plasminogen activator), impaired barrier function, and production of large quantities of proinflammatory and proallergic cytokines, including thymic stromal lymphopoietin. Collectively, we put forth a model in which the esophagus is normally equipped as an anti-inflammatory sensing organ and that defects in this pathway, mediated by epithelial protease/protease inhibitor imbalances, unleash inflammatory responses resulting in disorders, such as EoE.

Project description:ObjectivesEosinophilic esophagitis (EoE) is a chronic inflammatory condition that causes esophageal remodeling and stricture formation. We compared the clinical course of symptoms, endoscopic findings, histology, and changes in phenotype over time in EoE patients with inflammatory and fibrostenotic phenotypes.MethodsData were obtained from EoE patients from three medical centers and followed prospectively. Endoscopic features and histology from index and follow-up endoscopies were recorded. Behavior was classified as inflammatory if endoscopic findings demonstrated furrows or white plaques and as fibrostenotic if endoscopic findings included fixed rings or strictures.ResultsTwo hundred and fifty-six EoE patients were included in the analysis. The mean age was 32±18 years, 25% of patients were <18 years, 89% of patients were Caucasians, and 74% of patients were male. The mean duration of symptoms before diagnosis was 6.8±7.2 years with a follow-up of 1.7±1.9 years (maximum follow-up of 12 years). Fifty-four percent of patients presented with fibrostenotic EoE, whereas 46% presented with inflammatory EoE. Patients with inflammatory disease were younger than those with fibrostenotic disease (24±19 vs. 39±15 years, P<0.001). Patients with fibrostenotic disease had a longer duration of symptoms than those with inflammatory disease (8.1±7.7 vs. 5.3±6.3 years, P=0.002). Over the study period, 47 (18%) had remission of inflammatory EoE, 68 (27%) continued to have inflammatory disease, 74 (29%) continued to have fibrostenotic disease, 65 (25%) fibrostenotic patients had regression of fibrosis, and 2 patients (1%) progressed from inflammatory disease to fibrostenotic disease. Patients who had regression from their fibrostenosis were more likely than patients who continued to demonstrate fibrostenosis to have a decrease in proximal (54% vs. 32%, P<0.001) and distal (70% vs. 38%, P<0.001) eosinophilia.ConclusionsMost EoE patients maintained their phenotype or had an improvement with <1% progressing from inflammatory to fibrostenosis. This suggests that early therapeutic strategies aimed at controlling inflammation may interrupt, decrease, or prevent the remodeling fibrosis in EoE.

Dataset Information

Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-?.

Publications

Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α.

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