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

• Published in: Nature communications 2024-01, Vol.15 (1), p.913-14, Article 913
• Main Authors: Francis, Luc, McCluskey, Daniel, Ganier, Clarisse, Jiang, Treasa, Du-Harpur, Xinyi, Gabriel, Jeyrroy, Dhami, Pawan, Kamra, Yogesh, Visvanathan, Sudha, Barker, Jonathan N., Smith, Catherine H., Capon, Francesca, Mahil, Satveer K.
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/21; 14; 14/32; 38; 38/77; 38/91; 631/114; 631/250/127/1213; 631/250/2502; 631/250/256/2515; 631/250/347; Fibroblasts; Gene expression; Gene sequencing; Humanities and Social Sciences; Hybridization; Immunosuppressive agents; Inflammation; Inhibitors; Interleukin 23; Interleukin 24; Keratinocytes; multidisciplinary; Psoriasis; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Skin diseases; Transcriptomics; Wnt protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-44994-w

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. Single cell profiling of tissue from patients undergoing therapy has the potential to identify drug-induced immune changes. Here the authors show a skin scRNA-seq study of psoriasis patients treated with an IL-23 inhibitor and characterize changes in cell states during early treatment.