IL-13-induced STAT3-dependent signaling networks regulate esophageal epithelial proliferation in eosinophilic esophagitis.

Eosinophilic esophagitis, epithelium, proliferation, basal zone hyperplasia, STAT3, SFRP1, bioinformatics

Journal

The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002

Informations de publication

Date de publication:
Dec 2023
Historique:
received: 06 01 2023
revised: 11 07 2023
accepted: 21 07 2023
pubmed: 1 9 2023
medline: 1 9 2023
entrez: 31 8 2023
Statut: ppublish

Résumé

Basal zone hyperplasia (BZH) and dilated intercellular spaces (DISs) are thought to contribute to the clinical manifestations of eosinophilic esophagitis (EoE); however, the molecular pathways that drive BZH remain largely unexplored. We sought to define the role of IL-13-induced transcriptional programs in esophageal epithelial proliferation in EoE. We performed RNA sequencing, bioinformatics, Western blot, reverse transcriptase quantitative PCR, and histologic analyses on esophageal biopsies from healthy control and patients with EoE, primary esophageal cells derived from patients with EoE, and IL-13-stimulated esophageal epithelial keratinocytes grown at the air-liquid interface (EPC2-ALI). Genetic (shRNA) and pharmacologic (proteolysis-targeting chimera degrader) approaches and in vivo model of IL-13-induced esophageal epithelial remodeling (Krt5-rtTA x tetO-IL-13Tg) were used to define the role of signal transducer and activator of transcription 3 (STAT3) and STAT6 and secreted frizzled-related protein 1 (SFRP1) in esophageal epithelial proliferation. RNA-sequencing analysis of esophageal biopsies (healthy control vs EoE) and EPC2-ALI revealed 82 common differentially expressed genes that were enriched for putative STAT3 target genes. In vitro and in vivo analyses revealed a link between IL-13-induced STAT3 and STAT6 phosphorylation, SFRP1 mRNA expression, and esophageal epithelial proliferation. In vitro studies showed that IL-13-induced esophageal epithelial proliferation was STAT3-dependent and regulated by the STAT3 target SFRP1. SFRP1 mRNA is increased in esophageal biopsies from patients with active EoE compared with healthy controls or patients in remission and identifies an esophageal suprabasal epithelial cell subpopulation that uniquely expressed the core EoE proinflammatory transcriptome genes (CCL26, ALOX15, CAPN14, ANO1, and TNFAIP6). These studies identify SFRP1 as a key regulator of IL-13-induced and STAT3-dependent esophageal proliferation and BZH in EoE and link SFRP1

Sections du résumé

BACKGROUND BACKGROUND
Basal zone hyperplasia (BZH) and dilated intercellular spaces (DISs) are thought to contribute to the clinical manifestations of eosinophilic esophagitis (EoE); however, the molecular pathways that drive BZH remain largely unexplored.
OBJECTIVE OBJECTIVE
We sought to define the role of IL-13-induced transcriptional programs in esophageal epithelial proliferation in EoE.
METHODS METHODS
We performed RNA sequencing, bioinformatics, Western blot, reverse transcriptase quantitative PCR, and histologic analyses on esophageal biopsies from healthy control and patients with EoE, primary esophageal cells derived from patients with EoE, and IL-13-stimulated esophageal epithelial keratinocytes grown at the air-liquid interface (EPC2-ALI). Genetic (shRNA) and pharmacologic (proteolysis-targeting chimera degrader) approaches and in vivo model of IL-13-induced esophageal epithelial remodeling (Krt5-rtTA x tetO-IL-13Tg) were used to define the role of signal transducer and activator of transcription 3 (STAT3) and STAT6 and secreted frizzled-related protein 1 (SFRP1) in esophageal epithelial proliferation.
RESULTS RESULTS
RNA-sequencing analysis of esophageal biopsies (healthy control vs EoE) and EPC2-ALI revealed 82 common differentially expressed genes that were enriched for putative STAT3 target genes. In vitro and in vivo analyses revealed a link between IL-13-induced STAT3 and STAT6 phosphorylation, SFRP1 mRNA expression, and esophageal epithelial proliferation. In vitro studies showed that IL-13-induced esophageal epithelial proliferation was STAT3-dependent and regulated by the STAT3 target SFRP1. SFRP1 mRNA is increased in esophageal biopsies from patients with active EoE compared with healthy controls or patients in remission and identifies an esophageal suprabasal epithelial cell subpopulation that uniquely expressed the core EoE proinflammatory transcriptome genes (CCL26, ALOX15, CAPN14, ANO1, and TNFAIP6).
CONCLUSIONS CONCLUSIONS
These studies identify SFRP1 as a key regulator of IL-13-induced and STAT3-dependent esophageal proliferation and BZH in EoE and link SFRP1

Identifiants

DOI: 10.1016/j.jaci.2023.07.021 PMID: 37652141
pubmed: 37652141
pii: S0091-6749(23)01100-4
doi: 10.1016/j.jaci.2023.07.021
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1550-1568

Informations de copyright

Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Auteurs

Sahiti Marella (S)

Department of Pathology, University of Michigan, Ann Arbor, Mich.

Ankit Sharma (A)

Department of Pathology, University of Michigan, Ann Arbor, Mich; Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich.

Varsha Ganesan (V)

Department of Pathology, University of Michigan, Ann Arbor, Mich; Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich.

Daysha Ferrer-Torres (D)

Internal Medicine, University of Michigan, Ann Arbor, Mich.

James W Krempski (JW)

Department of Pathology, University of Michigan, Ann Arbor, Mich; Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich.

Gila Idelman (G)

Department of Pathology, University of Michigan, Ann Arbor, Mich; Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich.

Sydney Clark (S)

Department of Pathology, University of Michigan, Ann Arbor, Mich.

Zena Nasiri (Z)

College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Mich.

Simone Vanoni (S)

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Chang Zeng (C)

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Andrej A Dlugosz (AA)

Department of Dermatology, University of Michigan, Ann Arbor, Mich.

Haibin Zhou (H)

Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, Mich.

Shaomeng Wang (S)

Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, Mich.

Alfred D Doyle (AD)

Division of Allergy, Asthma and Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz.

Benjamin L Wright (BL)

Division of Allergy, Asthma and Immunology, Department of Medicine, Mayo Clinic Arizona, Scottsdale, Ariz; Section of Allergy and Immunology, Division of Pulmonology, Phoenix Children's Hospital, Phoenix, Ariz.

Jason R Spence (JR)

Internal Medicine, University of Michigan, Ann Arbor, Mich.

Mirna Chehade (M)

Mount Sinai Center for Eosinophilic Disorders, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Simon P Hogan (SP)

Department of Pathology, University of Michigan, Ann Arbor, Mich; Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich. Electronic address: sihogan@med.umich.edu.

Classifications MeSH