Activation of p38 MAPK mediates the induction of murine psoriatic dermatitis

Abstract

Listen

Translate article

Psoriasis is considered to be a Th17 type skin disorder. However, the trigger of Th17 response remains unknown. We previously reported that keratinocyte-specific double knockout of NF-kappaB isoforms developed psoriatic dermatitis. A lack of negative feedback pathway in NF-kappaB cascades is expected to lead to hyperactivation of other subordinate pathways in the epidermis and the development of psoriasis. One of the candidates is p38 mitogen activated protein kinase (MAPK) that shares the upper molecules in its signaling pathway with NF-kappaB and is activated in the epidermis in psoriasis. Nevertheless, the role of p38 in pathogenesis of psoriasis remains unexplored. Here, we report that daily topical application with a p38 activator, anisomycin, induces scaly erythema, epidermal thickening, dermal edema, and infiltration of leukocytes into the dermis and the cornified layer of the murine skin, which are similar to the clinical and histological findings of human psoriasis. The thickness of the treated ears was significantly increased by anisomycin treatment in a dose-dependent manner. The lesional gene expression levels of IL-24, IL-23p19, IL-22, and IL-17a, which are involved in the Th17 response, were markedly increased. The number of IL-17a-producing gamma delta T cells and neutrophils infiltrating into the skin was increased in the anisomycin-treated sites. Concordantly, all these responses were prevented by simultaneous treatment with BIRB 796, a kinase inhibitor specific to p38alpha. These results suggest that activation of p38 is sufficient to induce psoriatic dermatitis in mice, and that psoriasis is developed by the breakdown of skin homeostasis. This new animal model provides us a useful tool to explore a primary trigger of Th17 response in psoriasis.