Applying single-cell approaches to the study of immune responses in psoriasis

Psoriasis is an inflammatory skin disorder that can present with clinically distinct phenotypes. Plaque psoriasis (also known as psoriasis vulgaris or PsV) is the most common form of the disease and is characterised by scaly plaques that typically appear on the elbows, knees and lower back. While the advent of biologics has transformed PsV treatment, the mechanisms mediating drug-induced remission are not fully characterised. Rare variants of psoriasis also exist. Among those, palmoplantar pustulosis (PPP) manifests with painful pustules that affect the palms or the soles. The pathogenesis of PPP has been the subject of very limited investigations, so that the disease remains poorly understood and difficult to treat. Single-cell RNA sequencing (scRNA-seq) is a technique that allows the transcriptional profiling of individual cells, enabling a high-resolution characterization of immune responses in blood and solid tissues. Here, scRNA-seq was applied to the study of PPP pathogenesis and PsV drug response. In the first part of the project, peripheral blood mononuclear cells obtained from PPP cases and healthy controls were subject to scRNA-seq profiling. This demonstrated that the skin-homing T cells of affected individuals were markedly skewed towards a Th17 phenotype. The analysis also uncovered a double positive Th17/Th2 population, which was more abundant in cases compared to controls. Of note, pseudotime inference supported the presence of Th17 to Th2 plasticity. In the second part of the study, scRNA-seq was used to profile the skin of PsV individuals receiving the IL-23 inhibitor risankizumab. This analysis generated an atlas of PsV skin during disease and remission. It also revealed that IL-23 blockade influences cell-cell interactions, upregulating inhibitory signalling between regulatory T cells and myeloid cells. These results highlight the benefits of utilising scRNA-seq to further our understanding of psoriasis pathogenesis and disease resolution.