Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways

TLDR

Psoriasis vulgaris is an inflammatory skin disease driven by Th1 and Th17 cytokines, but the specific roles of IFN‑γ, IL‑17, and IL‑22 remain unclear. The study aimed to identify cytokines produced by skin‑resident T cells, map their receptors, and assess how these cytokines alter gene expression in receptor‑bearing cells. Researchers performed intracellular cytokine staining and flow cytometry to profile T‑cell cytokine production, used immunohistochemistry and double‑label immunofluorescence to localize receptors, and conducted gene‑array analysis of cytokine‑treated keratinocytes with FDR‑controlled moderated paired t‑tests. They found IL‑17, IL‑22, and IFN‑γ‑producing T cells and their receptors in normal skin; IL‑17 induced chemokines distinct from IFN‑γ, likely recruiting neutrophils, dendritic cells, and memory T cells, whereas IL‑22 suppressed keratinocyte differentiation genes and caused epidermal alterations, indicating IL‑17 is more proinflammatory and IL‑22 retards differentiation.

Abstract

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.