Interleukin-13 Promotes Accumulation of Esophageal Epithelial Mitochondria With Translational Implications for Eosinophilic Esophagitis.

BACKGROUND & AIMS: Metabolic and mitochondrial dysfunction have recently been implicated in eosinophilic esophagitis (EoE) pathogenesis. However, there is a need to define the influence of EoE-associated inflammatory cues upon mitochondrial biology, mechanisms mediating these effects, and the clinical significance of mitochondrial alterations in EoE.

METHODS

Mitochondria were evaluated in human biopsies, MC903/ovalbumin-induced murine EoE, and human esophageal keratinocytes stimulated with EoE-relevant cytokines. Mitochondrial mediators were assessed via quantitative reverse transcription polymerase reaction and Western blotting. Metabolism, mitochondrial membrane potential, and apoptosis were measured. Mitochondrial DNA (mtDNA)-encoded genes, ND1 and ND6 were assessed by quantitative polymerase chain reaction in DNA from culture media and circulating nucleic acids from human serum samples. Effects of Janus kinase (JAK) inhibitor ruxolitinib or genetic inhibition of signal transducer and activator of transcription (STAT)3 or STAT6 on mitochondria were assessed in vitro.

RESULTS

We identified evidence of increased mitochondria in esophageal mucosa of patients with EoE and mice with EoE-like inflammation. Interleukin (IL)-13 consistently induced mitochondrial accumulation in esophageal keratinocytes in vitro, and this response was associated with increased expression of mediators of mitochondrial biogenesis, fusion, and mitophagy. IL-13 suppressed mitochondrial respiration and adenosine triphosphate (ATP) production, without impacting membrane polarization or apoptosis. Patients with active EoE exhibited elevated serum mtDNA levels and upregulation of mediators of mtDNA-associated inflammatory signaling. Increased mitochondrial mass and accumulation of extracellular mtDNA in IL-13-treated esophageal keratinocytes were dependent on JAK/STAT signaling.

CONCLUSIONS

We identify IL-13 as a mediator of increased mitochondrial mass in EoE through JAK/STAT signaling. We further demonstrate that IL-13 promotes accumulation of extracellular mtDNA and that circulating mtDNA is elevated in patients with EoE.