Identification of anoctamin 1 (ANO1) as a key driver of esophageal epithelial proliferation in eosinophilic esophagitis

Simone Vanoni, Chang Zeng, Sahiti Marella, Jazib Uddin, David Wu, Kavisha Arora, Catherine Ptaschinski, Jianwen Que, Taeko Noah, Lisa Waggoner, Artem Barski, Andrey Kartashov, Mark Rochman, Ting Wen, Lisa Martin, Jason Spence, Margaret Collins, Vincent Mukkada, Phillip Putnam, Anjaparavanda NarenMirna Chehade, Marc E. Rothenberg, Simon P. Hogan

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Background: The pathology of eosinophilic esophagitis (EoE) is characterized by eosinophil-rich inflammation, basal zone hyperplasia (BZH), and dilated intercellular spaces, and the underlying processes that drive the pathologic manifestations of the disease remain largely unexplored. Objective: We sought to investigate the involvement of the calcium-activated chloride channel anoctamin 1 (ANO1) in esophageal proliferation and the histopathologic features of EoE. Methods: We examined mRNA and protein expression of ANO1 in esophageal biopsy samples from patients with EoE and in mice with EoE. We performed molecular and cellular analyses and ion transport assays on an in vitro esophageal epithelial 3-dimensional model system (EPC2-ALI) and murine models of EoE to define the relationship between expression and function of ANO1 and esophageal epithelial proliferation in patients with EoE. Results: We observed increased ANO1 expression in esophageal biopsy samples from patients with EoE and in mice with EoE. ANO1 was expressed within the esophageal basal zone, and expression correlated positively with disease severity (eosinophils/high-power field) and BZH. Using an in vitro esophageal epithelial 3-dimensional model system revealed that ANO1 undergoes chromatin modification and rapid upregulation of expression after IL-13 stimulation, that ANO1 is the primary apical IL-13–induced Cl transport mechanism within the esophageal epithelium, and that loss of ANO1-dependent Cl transport abrogated esophageal epithelial proliferation. Mechanistically, ANO1-dependent regulation of basal cell proliferation was associated with modulation of TP63 expression and phosphorylated cyclin-dependent kinase 2 levels. Conclusions: These data identify a functional role for ANO1 in esophageal cell proliferation and BZH in patients with EoE and provide a rationale for pharmacologic intervention of ANO1 function in patients with EoE.

Original languageEnglish
Pages (from-to)239-254.e2
JournalJournal of Allergy and Clinical Immunology
Volume145
Issue number1
DOIs
StatePublished - Jan 2020

Keywords

  • Eosinophilic esophagitis
  • IL-13
  • basal cell hyperplasia
  • chloride transport
  • esophageal epithelium

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