Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade

Luc Francis, Daniel McCluskey, Clarisse Ganier, Treasa Jiang, Xinyi Du-Harpur, Jeyrroy Gabriel, Pawan Dhami, Yogesh Kamra, Sudha Visvanathan, Jonathan N. Barker, Catherine H. Smith, Francesca Capon () and Satveer K. Mahil ()
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Luc Francis: King’s College London and Guy’s and St Thomas’ NHS Foundation Trust
Daniel McCluskey: King’s College London
Clarisse Ganier: King’s College London
Treasa Jiang: King’s College London and Guy’s and St Thomas’ NHS Foundation Trust
Xinyi Du-Harpur: King’s College London
Jeyrroy Gabriel: King’s College London
Pawan Dhami: King’s College London NIHR Biomedical Research Centre
Yogesh Kamra: King’s College London NIHR Biomedical Research Centre
Sudha Visvanathan: Boehringer Ingelheim Pharmaceuticals
Jonathan N. Barker: King’s College London and Guy’s and St Thomas’ NHS Foundation Trust
Catherine H. Smith: King’s College London and Guy’s and St Thomas’ NHS Foundation Trust
Francesca Capon: King’s College London
Satveer K. Mahil: King’s College London and Guy’s and St Thomas’ NHS Foundation Trust

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Biologic therapies targeting the IL-23/IL-17 axis have transformed the treatment of psoriasis. However, the early mechanisms of action of these drugs remain poorly understood. Here, we perform longitudinal single-cell RNA-sequencing in affected individuals receiving IL-23 inhibitor therapy. By profiling skin at baseline, day 3 and day 14 of treatment, we demonstrate that IL-23 blockade causes marked gene expression shifts, with fibroblast and myeloid populations displaying the most extensive changes at day 3. We also identify a transient WNT5A+/IL24+ fibroblast state, which is only detectable in lesional skin. In-silico and in-vitro studies indicate that signals stemming from these WNT5A+/IL24+ fibroblasts upregulate multiple inflammatory genes in keratinocytes. Importantly, the abundance of WNT5A+/IL24+ fibroblasts is significantly reduced after treatment. This observation is validated in-silico, by deconvolution of multiple transcriptomic datasets, and experimentally, by RNA in-situ hybridization. These findings demonstrate that the evolution of inflammatory fibroblast states is a key feature of resolving psoriasis skin.

Date: 2024
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DOI: 10.1038/s41467-024-44994-w

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