Proton pump inhibitors modulate esophageal epithelial barrier function and crosstalk with eosinophils

Eosinophilic esophagitis (EoE) is a chronic allergic disorder driven by type 2 inflammation, characterized by eosinophilic infiltration and esophageal epithelial abnormalities, including barrier dysfunction, basal cell hyperplasia, epithelial thickening, and loss of differentiation. Although proton pump inhibitor (PPI) therapy is frequently employed in the management of EoE and is known to reduce esophageal eosinophilia, improve barrier function, and exert anti-inflammatory effects, the precise mechanism by which PPIs modulate type 2 inflammation and epithelial integrity remains incompletely understood.

Air-liquid interface culture of esophageal epithelial cells was used to investigate the impact of the PPI omeprazole on barrier integrity in IL-13-treated cultures. Epithelial chemokine secretion was assessed following stimulation with IL-13 and omeprazole, and eosinophil migration from healthy human donors was evaluated using 3 μm pore-sized transwells. A co-culture system of epithelial cells and eosinophils was used to examine chemokine secretion, eosinophil adhesion, and activation marker expression.

Omeprazole treatment of IL-13-treated air-liquid interface (ALI) cultures restored barrier integrity compared with IL-13-treated ALI cultures and resulted in 186 differentially expressed genes. Omeprazole treatment reduced STAT6 phosphorylation, downregulated calpain 14 expression, and upregulated desmoglein-1 in IL-13-treated ALI samples. IL-13 treatment induced upregulation of Eotaxin-3, CXCL10, and periostin, which were downregulated by omeprazole. Eosinophils co-cultured with human esophageal epithelial cells in the presence of omeprazole had diminished CD11b, CD18, and CD69 expression compared to those cultured with IL-13 alone, and less eotaxin-3, CXCL10, CCL2, and CCL4 were recovered from the co-culture media.

Omeprazole diminished the effects of IL-13 in both the epithelial air-liquid interface model and eosinophil-epithelial co-cultures, alleviating barrier dysfunction, chemokine expression, and the upregulation of eosinophil adhesion markers.