Regulation of Imiquimod-Induced Mouse Psoriasis Development via Apoptosis Signal-Regulating Kinase 1 Potentially by Antagonizing Aryl Hydrocarbon Receptor Expression.

Imiquimod-induced skin inflammation is the most widely used psoriasis mouse model. Although p38 mitogen-activated protein kinase reportedly plays a role in the pathogenesis of psoriatic inflammation, the purpose of one of its upstream activators, apoptosis signal-regulating kinase 1 (ASK1), remains unclear. This study investigated the role of ASK1 and its molecular mechanism in the imiquimod-induced psoriasis model. Compared to wild-type mice, the ASK1 knockout (KO) mouse skin lesion showed a higher clinical score and a thicker epidermis. The mRNA expression of pro-inflammatory cytokines, such as IL-17 and TNF-α, was also higher. Notably, the expression of aryl hydrocarbon receptor (AhR), a sensor for xenobiotic chemicals that is expressed in the skin to strengthen the skin barrier and accelerate terminal differentiation of the epidermis-as well as its downstream molecule CYP1A1, but not NRF2-was increased in the ASK1 KO psoriatic skin lesion. Immunoprecipitation analysis, followed by Western blotting, revealed that ASK1 interacts with AhR in cells transfected with their respective expression vectors, potentially leading to reduced AhR expression. These results suggest that ASK1 negatively regulates the development of the imiquimod-induced mouse psoriasis model by interacting with AhR and presumably antagonizing the AhR-CYP1A1 axis.