Simone Vanoni1, Chang Zeng2, Sahiti Marella3, Jazib Uddin3, David Wu2, Kavisha Arora4, Catherine Ptaschinski3, Jianwen Que5, Taeko Noah6, Lisa Waggoner2, Artem Barski2, Andrey Kartashov2, Mark Rochman2, Ting Wen2, Lisa Martin7, Jason Spence8, Margaret Collins9, Vincent Mukkada10, Phillip Putnam10, Anjaparavanda Naren4, Mirna Chehade11, Marc E Rothenberg2, Simon P Hogan12. 1. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; PharmGenetix Gmbh, Niederalm-Anif, Austria. 2. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 3. Mary H Weiser Food Allergy Center and Department of Pathology, Ann Arbor, Mich. 4. Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 5. Department of Medicine, Columbia University Medical Center, New York, NY. 6. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Mary H Weiser Food Allergy Center and Department of Pathology, Ann Arbor, Mich. 7. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 8. Departments of Biomedical Engineering, Internal Medicine and Cell and Developmental Biology, University of Michigan, Ann Arbor, Mich. 9. Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 10. Division of Gastroenterology, Nutrition and Hepatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 11. Mount Sinai Center for Eosinophilic Disorders, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY. 12. Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Mary H Weiser Food Allergy Center and Department of Pathology, Ann Arbor, Mich. Electronic address: sihogan@med.umich.edu.
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.
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 channelanoctamin 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.
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