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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:142

Article

Zeng, Chang¹  Vanoni, Simone^1,5  Wu, David¹  Caldwell, Julie M.¹  Wheeler, Justin C.³  Arora, Kavisha²  Noah, Taeko K.¹  Waggoner, Lisa¹  Besse, John A.¹  Yamani, Amnah N.¹  Uddin, Jazib¹  Rochman, Mark¹  Wen, Ting¹  Chehade, Mirna⁶  Collins, Margaret H.³  Mukkada, Vincent A.⁴  Putnam, Philip E.⁴  Naren, Anjaparavanda P.²  Rothenberg, Marc E.¹  Hogan, Simon P.^1,7 

[1] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA

[2] Cincinnati Childrens Hosp Med Ctr, Div Pulm Med, Cincinnati, OH 45229 USA

[3] Cincinnati Childrens Hosp Med Ctr, Div Pathol & Lab Med, Cincinnati, OH 45229 USA

[4] Cincinnati Childrens Hosp Med Ctr, Div Gastroenterol Nutr & Hepatol, Cincinnati, OH 45229 USA

[5] Paracelsus Med Univ, Inst Pharmacol & Toxicol, Salzburg, Austria

[6] Icahn Sch Med Mt Sinai, Jaffe Food Allergy Inst, Mt Sinai Ctr Eosinophil Disorders, New York, NY 10029 USA

[7] Univ Michigan, Dept Pathol, Mary H Weiser Food Allergy Ctr, Michigan Med, 109 Zina Pitcher Pl, Ann Arbor, MI 48109 USA

关键词: Solute carrier family 9;    subfamily A;    member 3/sodium-hydrogen exchanger member 3;    ion transport;    eosinophilic esophagitis;    dilated intercellular spaces;    IL-13;   

DOI  :  10.1016/j.jaci.2018.03.017

来源: Elsevier

【 摘 要 】

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 pHi 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.

【 授权许可】

Free