Il-17e (Il-25) Enhances Innate Immune Responses During Murine Skin Inflammation

IL-17E (IL-25) is a member of the IL-17 cytokine family involved in the promotion of type 2 immune responses. Recently, IL-17E has been reported to be upregulated in distinct skin inflammatory diseases such as psoriasis, atopic and contact dermatitis. We assessed the role played by IL-17E in skin inflammation. Here we show that IL-17E induces skin inflammation in vivo, characterized by the expression of innate immune response genes and the recruitment of innate immune cells, particularly neutrophils. Genetic deletion or IL-17E neutralization ameliorated skin inflammation induced by imiquimod application, or tape-stripping, with reductions in neutrophil and macrophage infiltration as assessed by t-SNE-guided multiparameter flow cytometry analysis, in mice. In man, IL-17E promotes the recruitment of neutrophils via activation of macrophages in a p38-dependent mechanism. In addition, IL-17E is up-regulated in neutrophil-rich inflammatory skin diseases, such as pyoderma gangrenosum and acute generalized exanthematous pustulosis. Our data demonstrate a role for IL-17E in skin inflammation, which is unrelated to the development of type 2 immune reactions. We propose that IL-17E is an important common denominator of chronic skin inflammation promoting innate immune cell recruitment and activation.