Summary Background Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines, yet the relative contribution of interferon (IFN)-γ, interleukin (IL)-17 and IL-22 on disease pathogenesis is still unknown. Objectives In this study, we sought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors. Methods We used intracellular cytokine staining and flow cytometry to evaluate T cell cytokine production, and immunohistochemistry and double-label immunofluorescence to localize cytokine receptors in skin. Gene array analysis of cytokine-treated keratinocytes was performed using moderated paired t-test controlling for false discovery rate using the Benjamini–Hochberg procedure. Results We demonstrate that T-helper cells producing IL-17, IL-22 and/or IFN-γ, as well as the cells bearing cognate cytokine receptors, are present in normal human skin. Keratinocytes stimulated with IL-17 expressed chemokines that were different from those induced by IFN-γ, probably contributing to the influx of neutrophils, dendritic cells and memory T cells into the psoriatic lesion. In contrast, IL-22 downregulated genes associated with keratinocyte differentiation and caused epidermal alterations in an organotypic skin model. Conclusions Our results suggest that the Th17 cytokines IL-17 and IL-22 mediate distinct downstream pathways that contribute to the psoriatic phenotype: IL-17 is more proinflammatory, while IL-22 retards keratinocyte differentiation.

Macrophages are important cells of the innate immune system, and their study is essential to gain greater understanding of the inflammatory nature of psoriasis. We used immunohistochemistry and double-label immunofluorescence to characterize CD163+ macrophages in psoriasis. Dermal macrophages were increased in psoriasis compared to normal skin and were identified by CD163, RFD7, CD68, LAMP2, Stabilin-1, and MARCO. CD163+ macrophages expressed C-lectins CD206/MMR and CD209/DC-SIGN, as well as co-stimulatory molecules CD86 and CD40. They did not express mature DC markers CD208/DC-LAMP, CD205/DEC205 or CD83. Microarray analysis of in vitro derived macrophages treated with IFNγ showed that many of the genes upregulated in macrophages were found in psoriasis, including STAT1, CXCL9, Mx1 and HLA-DR. CD163+ macrophages produced inflammatory molecules IL-23p19 and IL-12/23p40 as well as TNF and iNOS. These data demonstrate that CD163 is a superior marker of macrophages, and identifies a subpopulation of “classically activated” macrophages in psoriasis. We conclude that macrophages are likely to be contributing to the pathogenic inflammation in psoriasis, a prototypical Th1 and Th17 disease, by releasing key inflammatory products.

To understand the development of new psoriasis lesions, we studied a group of moderate-to-severe psoriasis patients who experienced a relapse after ceasing efalizumab (anti-CD11a, Raptiva, Genentech). There were increased CD3+ T cells, neutrophils, CD11c+ and CD83+ myeloid dendritic cells (DCs), but no increase in CD1c+ resident myeloid DCs. In relapsed lesions, there were many CD11c+CD1c−, inflammatory myeloid DCs identified by TNFSF10/TRAIL, TNF, and iNOS. CD11c+ cells in relapsed lesions co-expressed CD14 and CD16 in situ. Efalizumab induced an improvement in many psoriasis genes, and during relapse, the majority of these genes reversed back to a lesional state. Gene Set Enrichment Analysis (GSEA) of the transcriptome of relapsed tissue showed that many of the gene sets known to be present in psoriasis were also highly enriched in relapse. Hence, on ceasing efalizumab, T cells and myeloid cells rapidly enter the skin to cause classic psoriasis.Trial registrationClinicaltrials.gov NCT00115076