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

Biologics 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 performed 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 demonstrated that IL-23 blockade causes marked gene expression shifts, with fibroblast and myeloid populations displaying the most extensive changes at day 3. We also identified a transientWNT5A+/IL24+fibroblast state, which was only detectable in lesional skin.In-silicoandin-vitrostudies indicated that signals stemming from theseWNT5A+/IL24+fibroblasts upregulated multiple inflammatory genes in keratinocytes. Importantly, the abundance ofWNT5A+/IL24+fibroblasts was significantly reduced after treatment. This observation was validatedin-silico, by deconvolution of multiple transcriptomic datasets, and experimentally, by RNAin-situhybridization. These findings demonstrate that the evolution of inflammatory fibroblast states is a key feature of resolving psoriasis skin.