207 IL-17E (IL-25) alters epidermal homeostasis in a matter distinct from IL-17A

Abstract

Our group has recently shown that keratinocyte-derived IL-17E (IL-25), one of six IL-17 isoforms, is overexpressed in lesional psoriatic skin. The presence of a complete receptor for IL-17E at the keratinocyte surface indicates the potential autocrine mode of action of the cytokine. We therefore aimed at addressing the influence of IL-17E on the functions of human primary keratinocytes. First, IL-17E, but not IL-17A, promoted the proliferation of keratinocytes as assessed by WST-1 proliferation assay and crystal violet staining. Surprisingly, IL-17E addition to cultured keratinocytes resulted in the concomitant up-regulation of differentiation-associated gene transcripts (i.e. keratin 10, loricrin and filaggrin), while their expression was either inhibited or not changed by IL-17A. Immunohistochemical analysis of in vitro reconstituted 3D epidermal equivalents confirmed these results. IL-17E, contrary to IL-17A, was instead not involved in the induction of an antimicrobial response. Moreover, time-lapse analysis of cell movement showed that IL-17E particularly influences cell motility increasing both cell speed and displacement. This was associated with specific changes in actin cytoskeleton organization and regulation of proteins involved in the focal contacts assembly such as vinculin. Altogether, our data point towards an important role for IL-17E in the epidermal phenotype of psoriasis; this role is clearly distinct from the role of IL-17A. Our results also reveal a possible effect of IL-17E beyond psoriasis, in disorders characterized by epidermal alterations as well as in the wound healing process.