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

Abstract

Biologic drugs targeting the IL-23/IL-17 axis have transformed outcomes for people living with psoriasis, allowing most patients to achieve skin clearance. Despite the potential to reveal fundamental regulators of skin homeostasis, the early mechanisms of action of these drugs remain poorly understood. Here, we performed longitudinal single-cell RNA sequencing in individuals with psoriasis who had been successfully treated with 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 identified a transientWNT5A+/IL24+fibroblast state, which was only detectable in lesional skin. The study of ligand-receptor interactions revealed that pro-inflammatory signals stemming from theseWNT5A+/IL24+fibroblasts upregulated multiple genes in differentiated 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 of additional skin samples. These findings demonstrate that the evolution of inflammatory fibroblast states is a key feature of resolving psoriasis skin.