Vasoactive Intestinal Peptide Receptor, CRTH2, Antagonist Treatment Improves Eosinophil and Mast Cell-Mediated Esophageal Remodeling and Motility Dysfunction in Eosinophilic Esophagitis

Author:

Yadavalli Chandra Sekhar1ORCID,Upparahalli Venkateshaiah Sathisha1,Verma Alok K.2,Kathera Chandrasekhar1ORCID,Duncan Pearce S.3,Vaezi Michael4,Paul Richard J.5,Mishra Anil1

Affiliation:

1. Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, School of Medicine, Tulane University, New Orleans, LA 70112, USA

2. Division of Gastroenterology, Cincinnati Childrens Medical Center, Cincinnati, OH 45229, USA

3. Division of Gastroenterology, School of Medicine, Tulane University, New Orleans, LA 70118, USA

4. Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, TN 37232, USA

5. Division of Physiology, Cincinnati University, Cincinnati, OH 45220, USA

Abstract

Background and Aims: Ultrasonography has shown that eosinophils accumulate in each segment of the esophageal mucosa in human EoE, ultimately promoting esophageal motility dysfunction; however, no mechanistic evidence explains how or why this accumulation occurs. Methods: Quantitative PCR, ELISA, flow cytometry, immunostaining, and immunofluorescence analyses were performed using antibodies specific to the related antigens and receptors. Results: In deep esophageal biopsies of EoE patients, eosinophils and mast cells accumulate adjacent to nerve cell-derived VIP in each esophageal segment. qRT-PCR analysis revealed five- to sixfold increases in expression levels of VIP, CRTH2, and VAPC2 receptors and proteins in human blood- and tissue-accumulated eosinophils and mast cells. We also observed a significant correlation between mRNA CRTH2 levels and eosinophil- and nerve cell-derived VIPs in human EoE (p < 0.05). We provide evidence that eosinophil and mast cell deficiency following CRTH2 antagonist treatment improves motility dysfunction in a chronic DOX-inducible CC10-IL-13 murine model of experimental EoE. Conclusions: CRTH2 antagonist treatment is a novel therapeutic strategy for inflammatory cell-induced esophageal motility dysfunction in IL-13-induced chronic experimental EoE.

Funder

NIH

Publisher

MDPI AG

Reference88 articles.

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