SLC9A3/NHE3 dysregulation and dilated intercellular spaces in eosinophilic esophagitis

Publication date: Available online 4 May 2018
Source:Journal of Allergy and Clinical Immunology
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 Collins, Vincent Mukkada, Philip Putnam, Anjaparavanda P. Naren, Marc E. Rothenberg, Simon P. Hogan
BackgroundEosinophilic esophagitis (EoE) is characterized by histopathologic modifications of esophageal tissue including eosinophil-rich inflammation, basal zone hyperplasia (BZH) and dilated intercellular spaces (DIS). The underlying molecular processes that drive the histopathologic features of EoE remain largely unexplored.ObjectiveTo investigate the involvement of SLC9A3 in esophageal epithelial [pH]i and DIS formation and the histopathological features of EoE.MethodsWe examined expression of esophageal epithelial gene networks associated with regulation of intracellular pH ([pH]i) in the EoE transcriptome of primary esophageal epithelial cells and an in vitro esophageal epithelial 3D model system (EPC2-ALI). Molecular and cellular analyses and ion transport assays were employed to evaluate expression and function of SLC9A3.ResultsWe identified altered expression of gene networks associated with regulation of intracellular pH ([pH]i) and acid protective mechanisms in esophageal biopsies from pediatric patients with EoE (normal n = 6, EoE n = 10). The most dysregulated gene central to regulating [pH]i was SLC9A3. SLC9A3 expression was increased within the basal layer of esophageal biopsies from patients with EoE and that expression positively correlated with disease severity (eosinophils/HPF) and DIS (normal n = 10, EoE n = 10). Analyses of esophageal epithelial cells revealed IL-13–induced, STAT6-dependent SLC9A3 expression and Na⁺-dependent proton secretion and that SLC9A3 activity positively correlated 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.ConclusionsSLC9A3 plays a functional role in DIS formation and pharmacologic interventions targeting SLC9A3 function may suppress the histopathologic manifestations in EoE.

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Teaser

IL13-induced SLC9A3/NHE3 upregulation in Eosinophilic Esophagitis leads to increased intracellular pH, and contributes to the dilated intercellular spaces (DIS) formation.


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