The role of the proinflammatory cytokines IL-17, IL-6 and IL-1 in (IMQ-induced) psoriasis
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Abstract
Psoriasis vulgaris is the most common form of the inflammatory skin disease psoriasis and leads to the formation of red, scaly plaques, mainly on the knees, elbows and scalp. Psoriasis affects 2-4% of the population worldwide and is associated with involvement of different immune cells (e.g. T cells and myeloid cells) and proinflammatory cytokines, for example IL-17, IL-6 or IL-1. Here, we used different transgene mouse models to examine the function of these cytokines and the respective receptors in more detail for their role in psoriatic disease.
Our lab recently established a novel mouse model where IL-17A is specifically overexpressed in keratinocytes (K14-IL-17Aind/ mice), which leads to skin inflammation showing many hallmarks of human psoriasis. As it was already shown that neutralization of IL-6 in those mice led to an improvement of the psoriatic phenotype, we also investigated the impact of anti-IL-17A treatment in this thesis. We could demonstrate that also the neutralization of IL-17A resulted in a partially improved disease severity. Moreover, the sera of treated K14-IL-17Aind/ mice displayed significantly reduced IL-17A levels compared to controls. Further, the treatment did result in an improved PASI score and less spleen-infiltrating myeloid cells. Hence, the results indicate a positive effect of the treatment. This we also confirmed by an anti-IL-17A treatment of wild type (wt) mice in the model of IMQ-induced psoriasis where the treatment also reduced the PASI score. IMQ is the active compound of AldaraTM cream and serves as a TLR7/8 agonist. Its topical application to the skin leads to a psoriasis-like skin disease, also in terms of the involved cytokines and infiltrating cells.
The role of IL-6 signaling in the psoriasis-like disease was investigated by deleting the membrane-bound IL-6Rα specifically in myeloid cells (IL-6RαΔmyel). Treating these mice with IMQ resulted in comparable disease severity as in wt mice. These findings could indicate that the effect of the deletion might be compensated by the soluble form of the receptor or by other cytokines of the gp130 family with redundant activities.
Interestingly, IL-1 signaling also seems to have a strong involvement in psoriasis-like disease, as
Il1r2-/- mice treated with IMQ exhibited significantly more myeloid cells than wt mice. To identify which cells are responsible for the observed phenotype, mice with a tissue specific deletion of IL-1R2 in T cells (Il1r2ΔT) and neutrophils (Il1r2ΔN) were analyzed in the same model. As none of these mouse strains showed differences compared to wt mice during IMQ treatment, neither neutrophils, nor T cells seemed to be responsible for the initial observed findings. Also here compensation by the soluble form of IL-1R2 should be considered.
The results of this thesis underline the neutralization of IL-17A being a promising treatment option for psoriasis. In addition, our findings regarding the role of the cytokines IL-6 and IL-1, could lead to the discovery of new drug targets for the treatment of this inflammatory skin disease.