Establishment of a novel murine model of psoriasis by activating p38 MAPK pathway

Experimental and clinical evidence has strongly suggested that the activation of the IL-23-IL-17 axis is essential in the development of psoriasis, which is considered to be initiated by external stresses to the epidermis. However, a molecular cue, which is attributed to the epidermal stresses and specifically induces the activation of the IL-23-IL-17 axis, remains to be clarified. It is of note that the activation of p38 was reported in the epidermal keratinocytes of psoriasis patients and its animal models. We therefore hypothesized that the activation of p38 in the epidermis in response to various stresses is a primary cue for the activation of the IL-23-IL-17 axis, and the subsequent development of psoriasis. We initially found that the treatment with a chemical p38 activator anisomycin rapidly induces the expression of psoriasis-related epidermal mediators in mouse and human primary cultured keratinocytes. We next examined whether epicutaneous application of anisomycin specifically develops psoriatic dermatitis in mice. Strikingly, daily topical treatment with anisomycin induced a dose-dependent increase in the ear thickness, scaly erythema with acanthosis, expression of the IL-23-IL-17 axis genes, and infiltration of neutrophils and IL-17A-producing T cells, all of which are a key signature in human psoriasis. Consistently, we found a reduced response to anisomysin in IL-17-defient mice, which indicates a critical role of IL-17 in this anisomysin-induced skin inflammation. Furthermore, the treatment with a p38alpha-specific inhibitor BIRB796 attenuated all these responses in vitro and in vivo. Taken together, our work indicates that the epidermal activation of p38 is a molecular cue to activate the IL-23-IL-17 axis, sufficient to induce psoriatic dermatitis.