Interferon-γ Signaling in Eosinophilic Esophagitis Affects Epithelial Barrier Function and Programmed Cell Death

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Eosinophilic esophagitis (EoE) involves eosinophil-driven inflammation and tissue changes in the esophagus.
• Previous studies noted increased interferon (IFN) response signature genes (ISGs) in EoE tissues.
• The specific cellular sources of IFN and their effects on esophageal epithelium in EoE are not fully understood.

Purpose of the Study:

• To investigate the expression of IFN and ISGs in EoE using single-cell RNA sequencing (scRNA-seq).
• To explore the impact of IFN-α and IFN-γ on esophageal epithelial cell function.
• To identify the cell types responsible for the IFN response in EoE.

Main Methods:

• scRNA-seq analysis of epithelial cells from EoE patients.
• Confirmatory bulk RNA-seq on isolated epithelial cells.
• Organoid models to assess the functional effects of IFN-α and IFN-γ on epithelial cells.

Main Results:

• Elevated ISG expression was observed in epithelial cells of active EoE patients, correlating with disease severity.
• IFN-α and IFN-γ treatments dose-dependently reduced esophageal organoid formation and size.
• IFN-γ demonstrated a significant impact on epithelial barrier function and caspase activity, with high IFNG expression noted in CD8+ T cells.

Conclusions:

• Interferons, particularly IFN-γ, are central to esophageal epithelial cell dysfunction in EoE.
• These findings highlight the role of IFN-γ in altering gene expression, differentiation, and barrier integrity.
• Understanding cytokine signaling in EoE may explain patient variability and treatment responses.