Integrated single-cell and spatial transcriptomics reveals heterogeneity of fibroblast and pivotal genes in psoriasis

Psoriasis, which is one of the most common skin diseases, involves an array of complex immune constituents including T cells, dendritic cells and monocytes. Particularly, the cytokine IL17A, primarily generated by TH17 cells, assumes a crucial function in the etiology of psoriasis. In this study, a comprehensive investigation utilizing bulk RNA analysis, single-cell RNA sequencing, and spatial transcriptomics was employed to elucidate the underlying mechanisms of psoriasis. Our study revealed that there is an overlap between the genes that are differentially expressed in psoriasis patients receiving three anti-IL17A monoclonal antibody drugs and the genes that are differentially expressed in lesion versus non-lesion samples in these patients. Further analysis using single-cell and spatial data from psoriasis samples confirmed the expression of hub genes that had low expressions in psoriasis tissue but were up-regulated after anti-IL17A treatments. These genes were found to be associated with the treatment effects of brodalumab and methotrexate, but not adalimumab, etanercept, and ustekinumab. Additionally, these genes were predominantly expressed in fibroblasts. In our study, fibroblasts were categorized into five clusters. Notably, hub genes exhibited predominant expression in cluster 3 fibroblasts, which were primarily engaged in the regulation of the extracellular matrix and were predominantly located in the reticular dermis. Subsequent analysis unveiled that cluster 3 fibroblasts also established communication with epithelial cells and monocytes via the ANGPTL-SDC4 ligand-receptor configuration, and their regulation was governed by the transcription factor TWIST1. Conversely, cluster 4 fibroblasts, responsible for vascular endothelial regulation, were predominantly distributed in the papillary dermis. Cluster 4 predominantly engaged in interactions with endothelial cells via MDK signals and was governed by the distinctive transcription factor, ERG. By means of an integrated analysis encompassing bulk transcriptomics, single-cell RNA sequencing, and spatial transcriptomics, we have discerned genes and clusters of fibroblasts that potentially contribute to the pathogenesis of psoriasis.