377 IL-17E favors the recruitment of neutrophils in psoriasis via macrophage activation

Abstract

Psoriasis vulgaris is a chronic recurrent inflammatory skin disease, affecting approximately 2% of the population. We have recently found that IL-17E (also known as IL-25), a member of the IL-17 cytokine family, is over-expressed in lesional psoriatic skin when compared to non lesional and healthy donors. Within the psoriatic plaque, macrophages represent an important proportion of IL-17E+ cells infiltrating the dermis. In this study we investigated the biological effects of IL-17E on macrophages in psoriasis. By confocal analysis of the lesional skin form 6 psoriatic patients, we found that IL-17E co-localized in macrophages with its receptor IL-17RB and clathrin, suggesting its in vivo internalization via a receptor-induced clathrin-mediated mechanism. Phenotypically, IL-17E+ macrophages exhibit a mixed M1/M2 phenotype, being positive for both CLEC5A and CD163L1 markers. In vitro, monocyte-derived macrophages were unable to produce IL-17E mRNA and internalized the cytokine in a time-dependent manner. The internalization process was blocked in the presence of a clathrin specific inhibitor. M2-polarized macrophages, but not M1, expressed high level of IL-17RB and responded to IL-17E dose-dependently by increasing the mRNA levels of inflammatory cytokines and chemokines preferentially favoring the recruitment of neutrophils. Of note, the number of IL-17E+ cells in lesional skin correlated with the PASI score and the number of neutrophils, while being inversely proportional to the number of infiltrating T cells. In vivo, intra-dermal injection of rmIL-17E in C57BL/6 mice induced severe dermal inflammation with neutrophil and eosinophil infiltration, in addition to a hyperplastic epidermis, compared to the PBS control group. Our data provide strong evidence for a novel pro-inflammatory role of IL-17E in psoriasis, possibly via activation of macrophages leading to a preferential recruitment of neutrophils.