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

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-alpha and LOX expression in patients with EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNF-alpha-mediated epithelial LOX upregulation was recapitulated in 3-dimensional organoids and coculture experiments. We find that fibroblast-derived TNF-alpha stimulates epithelial LOX expression through activation of nuclear factor kappa B and TGF-beta-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-alpha secretion. Esophageal epithelial LOX might have a role in the development of fibrosis with substantial translational implications.