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bioRxiv · 10.1101/2024.08.22.609219

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

Gautam, R.·Lal, M.·Carroll, M. C.·Mrozek, Z.·Trachsel, T.·Beers, J.·Ruffner, M. A.
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Abstract

BackgroundEosinophilic esophagitis (EoE) is a chronic allergic disease characterized by esophageal dysfunction, type-2 inflammation, and esophageal eosinophilic infiltrate. While proton pump inhibitor (PPI) therapy is commonly used for EoE management, the underlying mechanism of action remains unclear. MethodsAir-liquid interface culture of esophageal epithelial cells was employed 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 the migration of eosinophils from healthy human donors was evaluated using 3 {micro}m pore-sized transwells. A co-culture system of epithelial cells and eosinophils was employed to study chemokine secretion and eosinophil adhesion and activation markers. ResultsOmeprazole treatment in the IL-13-treated air-liquid interface (ALI) model resulted in 186 differentially expressed genes and restored barrier integrity compared to ALI treated with IL-13 alone. Omeprazole treatment reduced STAT6 phosphorylation, downregulated calpain 14, and upregulated desmoglein-1 in the IL-13-treated air-liquid interface samples. IL-13-induced upregulation of Eotaxin-3, CXCL10, and periostin, but this was downregulated by omeprazole. Further, the expression of CD11b, CD18, and CD69 was lower on eosinophils from omeprazole-treated epithelial-eosinophil co-cultures, which also had lower levels of eotaxin-3, CXCL10, CCL2, and CCL4. ConclusionOmeprazole reduced the effects of IL-13 in both the epithelial air-liquid interface model and eosinophil-epithelial co-cultures, reducing barrier dysfunction, chemokine expression, and upregulation of eosinophil adhesion markers.

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Gautam, R., Lal, M., Carroll, M. C., Mrozek, Z., Trachsel, T., Beers, J., Ruffner, M. A.. 2024-08-23. Proton pump inhibitors modulate esophageal epithelial barrier function and crosstalk with eosinophils. https://doi.org/10.1101/2024.08.22.609219

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