Basal IFN-λ2/3 expression mediates tight junction formation in human epithelial cells

Area of Science:

• Immunology
• Cell Biology
• Epithelial Biology

Background:

• Type-III interferons (IFN-λs) are vital for antiviral defense and maintaining intestinal epithelial barrier function.
• Basal IFN-λ expression occurs even without pathogens, but its regulation and function remain unclear.

Purpose of the Study:

• To elucidate the mechanisms regulating basal IFN-λ expression.
• To determine the functional role of basal IFN-λ expression in epithelial barrier development and maintenance.

Main Methods:

• Investigated basal IFN-λ2/3 expression in cellular epithelium.
• Utilized cGAS-STING and Hippo pathway signaling analysis.
• Assessed epithelial barrier function, tight junction formation, and Claudin-2 expression.

Main Results:

• Basal IFN-λ2/3 expression correlates with intact epithelial tight junctions and barrier function.
• Expression depends on cGAS-STING-mediated mitochondrial DNA detection.
• The Hippo pathway inhibits basal IFN-λ2/3 at low cell densities.
• IFN-λ2/3 suppresses Claudin-2, promoting barrier formation during cell confluency.
• Absence of basal IFN-λ2/3 impairs tight junction development and barrier function.

Conclusions:

• Basal IFN-λ2/3 expression is essential for proper epithelial barrier formation and integrity.
• This pathway is regulated by cellular density and intrinsic signaling pathways (cGAS-STING, Hippo).
• IFN-λs play a critical role in maintaining epithelial homeostasis under steady-state conditions, beyond pathogen defense.