Interleukin-13-mediated alterations in esophageal epithelial mitochondria contribute to tissue remodeling in eosinophilic esophagitis

Abstract

BackgroundThe significance of mitochondria in EoE pathobiology remains elusive. ObjectiveTo 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. MethodsMitochondria were evaluated in human biopsies, MC903/Ovalbumin-induced murine EoE, and human esophageal keratinocytes. Esophageal keratinocytes were treated with EoE-relevant cytokines and JAK/STAT inhibitor ruxolitinib. To deplete mitochondria, 3D organoids generated from TFAMloxp/loxp mice were subjected ex vivo to Cre or siRNA against Transcription factor A, mitochondria (TFAM) was transfected into esophageal keratinocytes. Mitochondrial respiration, membrane potential, and superoxide levels were measured. ResultsWe 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. ConclusionsWe 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 ImplicationThese findings further lay a foundation for exploration of level of esophageal epithelial mitochondria as a predictive biomarker for response to dupilumab. Capsule summaryIL-13 promotes mitochondrial biogenesis in esophageal epithelium, contributing to impaired squamous cell differentiation.