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

Although atopic dermatitis (AD) has been reported to be a typical type 2 immune response disease, it is also an inflammatory skin disease that involves cytokines, such as Th1, Th17 and Th22. However, little is known about the mechanism by which the candidate cytokines, alone or in combination, are involved in AD pathology. Differences in cytokine balance, which contribute to the complexity of AD pathology, may influence the stratum corneum barrier function through tight junction (TJ) functional stability and contribute to disease severity. To confirm the regulatory mechanism of TJ protein expression in AD, we investigated the Th1 and Th17 pathways, which are the initiation factors of chronic AD pathology. We examined the effects of these cytokines on TJ protein expression in normal human epidermal keratinocytes in vitro, and also examined their function in a human skin equivalent model. We observed a time- and dose-dependent inhibitory effect of IFN-gamma on claudin-1 expression via the IFN-gamma receptor/JAK/STAT signalling pathway. IFN-gamma impaired TJ function in a human skin equivalent model. Moreover, we investigated co-stimulation with IL-17A, which is highly expressed in AD skin lesions and found that IL-17A restores IFN-gamma-induced TJ dysfunction. This restoration of TJ function was mediated by atypical protein kinase C zeta activation without recovery of TJ protein expression. These results are informative for personalized AD treatment via systemic therapies using anti-cytokine antibodies and/or JAK inhibitors.

Automated summary

The study revealed that IFN-gamma inhibits claudin-1 expression leading to TJ dysfunction, while IL-17A can restore IFN-gamma-induced TJ dysfunction by activating atypical protein kinase C zeta instead of recovering TJ protein expression. These findings provide insights for personalized AD treatment using systemic therapies with anti-cytokine antibodies and/or JAK inhibitors.