Interleukin-13-mediated alterations in esophageal epithelial mitochondria contribute to tissue remodeling in eosinophilic esophagitis
Year: 2025
Type: preprint
Abstract: Background: The significance of mitochondria in EoE pathobiology remains elusive. Objective: To determine the impact of EoE inflammatory mediators upon mitochondrial biology in esophageal epithelium, the mechanisms mediating these effects, and their functional significance to EoE pathobiology. Methods: to Cre or siRNA against Transcription factor A, mitochondria (TFAM) was transfected into esophageal keratinocytes. Mitochondrial respiration, membrane potential, and superoxide levels were measured. Results: We find evidence of increased mitochondria in esophageal epithelium of patients with EoE and mice with EoE-like inflammation. In esophageal keratinocytes, IL-4 and IL-13 increase mitochondrial mass. IL-13 increases mitochondrial biogenesis in a JAK/STAT-dependent manner. In 3D organoids, IL-13 limits squamous cell differentiation (SCD), and this is blunted upon TFAM depletion. IL-13 decreases mitochondrial respiration and superoxide level, although mitochondria remain intact. IL-13-mediated suppression of superoxide was abrogated upon TFAM depletion in esophageal keratinocytes. Conclusions: We report that increased mitochondrial mass is a feature of EoE. Among EoE-relevant cytokines, IL-13 is the primary driver of increased mitochondrial mass in esophageal keratinocytes by promoting mitochondrial biogenesis in a JAK/STAT-dependent manner. IL-13-mediated accumulation of mitochondria impairs SCD in esophageal keratinocytes and also suppresses oxidative stress, a factor that is known to induce SCD. These findings identify a novel mechanism through which IL-13 promotes EoE-associated epithelial remodeling. Clinical Implication: These findings further lay a foundation for exploration of level of esophageal epithelial mitochondria as a predictive biomarker for response to dupilumab. Capsule summary: IL-13 promotes mitochondrial biogenesis in esophageal epithelium, contributing to impaired squamous cell differentiation.
Authors: Jazmyne L. Jackson, Reshu Saxena, Mary Grace Murray, Abigail J. Staub, Alena Klochkova, Travis H. Bordner, Courtney Worrell, Annie D. Fuller, John M. Crespo, Andres J. Klein-Szanto, John Elrod, Tatiana A. Karakasheva, Melanie Ruffner, Amanda B. Muir, Kelly A. Whelan
Language: English
Topic: Eosinophilic Esophagitis
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4409111982