385 IL-17E activates M2 macrophages to produce IL-8 in a p38 dependent manner and favor the recruitment of neutrophils in psoriatic skin

Abstract

Psoriasis vulgaris is a common chronic recurrent immune-mediated skin disease. We have recently found that IL-17E (i.e 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 having a mixed M1/M2 phenotype internalize IL-17E in a receptor induced clathrin-mediated mechanism. In this study we investigated the biological effects of IL-17E in psoriasis. In vitro M2-polarized macrophages, but not M1, responded to IL-17E by producing inflammatory cytokines (e.g. TNF and IL-6) and chemokines (e.g. IL-8 and MCP-1) typical expressed by M1 cells. Nuclear factor-kappa B (NF- κB), p38 and STAT3 were required for generating the IL-17E-dependent effects. Of note, IL-17E did not stimulate the production of cytokines/chemokines involved in T cell polarization and recruitment. Supernatants of IL-17E-stimulated M2 macrophages contained high levels of IL-8 and favored the attraction of neutrophils to a higher extent compared to supernatants of resting macrophages. Chemical p38 inhibition impaired IL-8 production and neutrophil chemotaxis in vitro. In vivo, intra-dermal injection of rmIL-17E in BALB/c mice induced severe dermal inflammation as assessed by immunohistological and FACS analysis, with increased neutrophil/eosinophil infiltration and reduced T-cell recruitment, compared to saline control group. Neutralization of IL-17E by intra-peritoneal injection of anti-IL-17E antibodies reduced the infiltration of neutrophils in a tape-stripping model. Consistent with the in vivo and in vitro data, the number of IL-17E+ cells in lesional skin correlated with the number of neutrophils, while being inversely proportional to the number of infiltrating T cells. Together, our data show that IL-17E favors the preferential recruitment of neutrophils via macrophage activation and define a novel pro-inflammatory role of IL-17E in psoriasis.