Fibrostenotic eosinophilic esophagitis may reflect epithelial lysyl oxidase induction by fibroblasts-derived tumor necrosis factor-α

Publication date: Available online 20 December 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Yuta Kasagi, Kara Dods, Joshua X. Wang, Prasanna M. Chandramouleeswaran, Alain J. Benitez, Fiona Gambanga, Jonathan Kluger, Tokunbo Ashorobi, Jonathan Gross, John W. Tobias, Andres J. Klein-Szanto, Jonathan M. Spergel, Antonella Cianferoni, Gary W. Falk, Kelly A. Whelan, Hiroshi Nakagawa, Amanda B. Muir

Abstract

Background

Fibrosis and stricture are major comorbidities in 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 RNA-sequencing, PCR assays and immunostaining in EoE patients, cytokine-stimulated esophageal three-dimensional (3D) organoids and fibroblast-epithelial cell co-culture, the latter coupled with fluorescence-activated cell sorting.

Results

Gene ontology and pathway analyses linked tumor necrosis factor (TNF)-α and LOX expression in EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNFα-mediated epithelial LOX upregulation was recapitulated in 3D organoids and co-culture experiments. We find fibroblast-derived TNFα stimulates epithelial LOX expression via activation of nuclear factor-κ B and transforming growth factor-β-mediated signaling. In patients, receiver operating characteristic analyses suggested that LOX upregulation indicates disease complications and fibrostenotic conditions in EoE.

Conclusions

There is a novel positive feedback mechanism in epithelial LOX induction via fibroblast-derived TNFα secretion. Esophageal epithelial LOX may have a role in the development of fibrosis with substantial translational implications.

Graphical abstract

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