Solute carrier family 9, subfamily A, member 3 (SLC9A3)/sodium-hydrogen exchanger member 3 (NHE3) dysregulation and dilated intercellular spaces in patients with eosinophilic esophagitis

Publication date: December 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 6

Author(s): Chang Zeng, Simone Vanoni, David Wu, Julie M. Caldwell, Justin C. Wheeler, Kavisha Arora, Taeko K. Noah, Lisa Waggoner, John A. Besse, Amnah N. Yamani, Jazib Uddin, Mark Rochman, Ting Wen, Mirna Chehade, Margaret H. Collins, Vincent A. Mukkada, Philip E. Putnam, Anjaparavanda P. Naren, Marc E. Rothenberg, Simon P. Hogan

Background

Eosinophilic esophagitis (EoE) is characterized by histopathologic modifications of esophageal tissue, including eosinophil-rich inflammation, basal zone hyperplasia, and dilated intercellular spaces (DIS). The underlying molecular processes that drive the histopathologic features of EoE remain largely unexplored.

Objective

We sought to investigate the involvement of solute carrier family 9, subfamily A, member 3 (SLC9A3) in esophageal epithelial intracellular pH (pH_i) and DIS formation and the histopathologic features of EoE.

Methods

We examined expression of esophageal epithelial gene networks associated with regulation of pH_i in the EoE transcriptome of primary esophageal epithelial cells and an in vitro esophageal epithelial 3-dimensional model system (EPC2-ALI). Molecular and cellular analyses and ion transport assays were used to evaluate the expression and function of SLC9A3.

Results

We identified altered expression of gene networks associated with regulation of pH_i and acid-protective mechanisms in esophageal biopsy specimens from pediatric patients with EoE (healthy subjects, n = 6; patients with EoE, n = 10). The most dysregulated gene central to regulating pH_i was SLC9A3. SLC9A3 expression was increased within the basal layer of esophageal biopsy specimens from patients with EoE, and expression positively correlated with disease severity (eosinophils/high-power field) and DIS (healthy subjects, n = 10; patients with EoE, n = 10). Analyses of esophageal epithelial cells revealed IL-13–induced, signal transducer and activator of transcription 6–dependent SLC9A3 expression and Na⁺-dependent proton secretion and that SLC9A3 activity correlated positively with DIS formation. Finally, we showed that IL-13–mediated, Na⁺-dependent proton secretion was the primary intracellular acid-protective mechanism within the esophageal epithelium and that blockade of SLC9A3 transport abrogated IL-13–induced DIS formation.

Conclusions

SLC9A3 plays a functional role in DIS formation, and pharmacologic interventions targeting SLC9A3 function may suppress the histopathologic manifestations in patients with EoE.

Graphical abstract

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