Interferon-γ downregulates tight junction function, which is rescued by interleukin-17A.

Area of Science:

• Immunodermatology
• Molecular Biology
• Skin Barrier Function

Background:

• Atopic dermatitis (AD) involves complex immune responses beyond typical type 2, including Th1, Th17, and Th22 cytokines.
• The precise mechanisms by which these cytokines influence AD pathology and skin barrier integrity, particularly tight junction (TJ) stability, remain incompletely understood.
• Cytokine imbalances are hypothesized to impact stratum corneum barrier function and disease severity in AD.

Purpose of the Study:

• To elucidate the regulatory mechanisms of TJ protein expression in AD.
• To investigate the effects of Th1 (IFN-γ) and Th17 (IL-17A) cytokines on TJ protein expression and function.
• To explore potential therapeutic strategies targeting cytokine pathways for AD.

Main Methods:

• In vitro studies using normal human epidermal keratinocytes exposed to IFN-γ and IL-17A.
• In vivo validation using a human skin equivalent model to assess TJ function.
• Analysis of signaling pathways, including IFN-γ receptor/JAK/STAT and atypical protein kinase C zeta.

Main Results:

• IFN-γ significantly inhibited claudin-1 expression in a time- and dose-dependent manner via the IFN-γ receptor/JAK/STAT pathway.
• IFN-γ impaired TJ function in the human skin equivalent model.
• IL-17A co-stimulation restored IFN-γ-induced TJ dysfunction, mediated by atypical protein kinase C zeta, without restoring TJ protein expression.

Conclusions:

• IFN-γ plays a critical role in compromising skin barrier integrity in AD through TJ disruption.
• IL-17A demonstrates a potential therapeutic role in restoring TJ function, independent of TJ protein levels.
• Findings support personalized AD treatment strategies involving anti-cytokine therapies and JAK inhibitors.