Psoriasis is a chronic inflammatory skin disorder effectively treated by blocking IL-17RA, a receptor chain used by several IL-17 family members, including IL-17E. Although IL-17A is critically involved in the pathogenesis of psoriasis, the contribution of IL-17E remains unknown. Here we show that IL-17E+ cells are more abundant than IL-17A+ cells in lesional psoriatic skin. IL-17E synthesis is increased in keratinocytes within psoriatic plaques, and macrophages having a mixed M1/M2 phenotype represent an important proportion of the IL-17E+ cells infiltrating the dermis. Mechanistically, macrophages do not synthetize but rather take up IL-17E via receptor-mediated clathrin-dependent endocytosis. Furthermore, monocyte-derived macrophages in vitro polarized in M2, but not M1, express the IL-17E receptor and respond to IL-17E by preferentially producing inflammatory cytokines and chemokines involved in neutrophil recruitment. Remarkably, IL-17E expression in lesional psoriatic skin correlates with the number of neutrophils while being inversely proportional to the number of infiltrating T cells. These data provide strong evidence for a proinflammatory role of keratinocyte-derived IL-17E in psoriasis, possibly via macrophage activation.
