The following is a summary of “Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis.,” published in the August 2024 issue of Allergy and Immunology by Ryan et al.

Understanding the role of epithelial cell metabolism in allergic inflammation is crucial for elucidating the mechanisms underlying the pathogenesis of eosinophilic esophagitis (EoE). Prior research has highlighted the absence of hypoxia-inducible factor 1-alpha (HIF-1α) signaling in EoE, contributing to esophageal epithelial dysfunction. However, the impact of HIF-1α-mediated metabolic regulation on esophageal allergy has not been thoroughly investigated. This study aimed to explore the role of HIF-1α in metabolic dysfunction affecting epithelial differentiation and barrier function in EoE. 

Researchers utilized RNA sequencing from biopsies of patients with EoE to examine the expression of genes related to mitochondrial metabolism, oxidative phosphorylation (OXPHOS), and glycolysis. Further, bioenergetics analysis using the Seahorse XF Analyzer was conducted on EPC2-hTERT cells to investigate metabolic processes involved in epithelial differentiation. Additionally, air-liquid interface cultures were employed to elucidate the metabolic dependencies required for epithelial differentiation. Transcriptomic data revealed increased expression of OXPHOS-associated genes in patients with EoE, a finding corroborated by complex V immunofluorescence in patient biopsies. 

In vitro, bioenergetic analysis demonstrated that differentiated epithelial cells were less dependent on OXPHOS than undifferentiated cells. HIF1A-knockdown EPC2-hTERT cells showed elevated OXPHOS potential and decreased glycolytic capacity, accompanied by a significant reduction in terminal markers of epithelial differentiation, such as involucrin. Pharmacological inhibition of glucose transport mimicked these effects, while restoration of HIF-1α activity using the pan-prolyl hydroxylase inhibitor DMOG reversed the phenotype and restored the expression of epithelial differentiation markers. These findings indicate that a predominant OXPHOS metabolic pattern in EoE, primarily due to impaired HIF-1α-mediated glycolysis, is associated with esophageal epithelial differentiation and function deficiencies.

Source: sciencedirect.com/science/article/pii/S0091674924008674