
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.22.609219
preprint
1
Article
Proton pump inhibitors modulate esophageal epithelial barrier function and crosstalk with eosinophils
Gautam Ravi http://orcid.org/0000-0001-5622-1345

Lal Megha http://orcid.org/0000-0002-9235-7255

Carroll Margaret C
Mrozek Zoe
Trachsel Tina
Beers Jarad
Ruffner Melanie A http://orcid.org/0000-0002-2943-9944

23 8 2024
2024.08.22.609219https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.22.609219
nihpp-2024.08.22.609219.pdf
Background: Eosinophilic 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. Methods: Air-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 μm pore-sized transwells. A co-culture system of epithelial cells and eosinophils was employed to study chemokine secretion and eosinophil adhesion and activation markers. Results: Omeprazole 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. Conclusion: Omeprazole 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.
==== Body
pmc
