Understanding the impact of risankizumab on keratinocyte-derived IL-23A in a novel organotypic 3D skin model containing IL-23A responsive and IL-17A producing γδ-T-cells

Abstract

Purpose

To study the effects of the anti-IL-23A antibody risankizumab on the IL-36γ/IL-23A/IL-17A signalling cascade we used a newly developed 3D skin model consisting of primary human keratinocytes, fibroblasts and γδ-T-cells.

Methods

In this in vitro study we developed new full-thickness 3D skin models containing normal human epidermal keratinocytes (NHEK), normal human dermal fibroblasts (NHDF) and IL-23A responsive and IL-17A producing γδ-T-cells. The effects of IL-36γ stimulation with and without risankizumab treatment on IL-23A and IL-17A expression were examined at the RNA and protein levels.

Results

In preliminary monolayer experiments stimulation of γδ-T-cells with IL-23A promoted the IL-17A expression that was inhibited after risankizumab treatment. Using 3D skin models containing γδ-T-cells, we found that stimulation with IL-36γ significantly increased not only IL-23A but also IL-17A expression. These effects were inhibited by concomitant treatment with risankizumab.

Conclusions

Our results showed that blockade of IL-23A has inhibitory effects on the IL-36γ/IL-23A feedforward loop. Our newly developed 3D skin model containing IL-23A responsive and IL-17A producing γδ-T-cells enables molecular analysis of targeted therapies aimed at the IL-36γ/IL-23A/IL-17A signalling cascade in psoriasis.

Keywords:

• IL-23/IL-17 axis
• IL-36
• 3D skin model
• γδ-T-cells
• anti-IL-23-antibody

Authors contributions

LH and PMA drafted the manuscript. LH and YM performed the experiments. LH, PMA, JMB and SH analysed and interpreted the data. JMB and SH designed the research study. All authors read, critically revised and approved the final manuscript.

Ethics statement

This study was conducted according to the Declaration of Helsinki Principles and was approved by the ethical committee of the University Hospital, RWTH Aachen, Germany (EK188/14). A written informed consent was obtained from all participants.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Additional information

Funding

This work was supported by a grant from AbbVie.