TY - JOUR
T1 - Identification of anoctamin 1 (ANO1) as a key driver of esophageal epithelial proliferation in eosinophilic esophagitis
AU - Vanoni, Simone
AU - Zeng, Chang
AU - Marella, Sahiti
AU - Uddin, Jazib
AU - Wu, David
AU - Arora, Kavisha
AU - Ptaschinski, Catherine
AU - Que, Jianwen
AU - Noah, Taeko
AU - Waggoner, Lisa
AU - Barski, Artem
AU - Kartashov, Andrey
AU - Rochman, Mark
AU - Wen, Ting
AU - Martin, Lisa
AU - Spence, Jason
AU - Collins, Margaret
AU - Mukkada, Vincent
AU - Putnam, Phillip
AU - Naren, Anjaparavanda
AU - Chehade, Mirna
AU - Rothenberg, Marc E.
AU - Hogan, Simon P.
N1 - Publisher Copyright:
© 2019 American Academy of Allergy, Asthma & Immunology
PY - 2020/1
Y1 - 2020/1
N2 - 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.
AB - 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.
KW - Eosinophilic esophagitis
KW - IL-13
KW - basal cell hyperplasia
KW - chloride transport
KW - esophageal epithelium
UR - http://www.scopus.com/inward/record.url?scp=85075884615&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2019.07.049
DO - 10.1016/j.jaci.2019.07.049
M3 - Article
C2 - 31647967
AN - SCOPUS:85075884615
SN - 0091-6749
VL - 145
SP - 239-254.e2
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 1
ER -