Single-cell RNA-Seq reveals the transcriptional landscape and heterogeneity of skin macrophages in Vsir-/- murine psoriasis

Abstract

Rationale: V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel inhibitory immune checkpoint molecule. Vsir^-/- mice have exacerbated psoriasis-like skin inflammation. The immune cell subsets involved in inflammation in Vsir^-/- psoriatic mice are largely unknown. We have used scRNA-seq as an unbiased profiling strategy to study the heterogeneity of immune cells at a single cell level in the skin of Vsir^-/- psoriatic mice. Methods: In the present study, the right ear and shaved back skin of wild type and Vsir^-/- mice were treated with IMQ for 5 consecutive days to induce psoriasis-like dermatitis. Then, the single-cell RNA sequencing analysis of mouse back skin lesions was performed using 10 × Genomics technique. Results: We identified 12 major cell subtypes among 23,258 cells. The major populations of the skin cells included macrophages, dendritic cells and fibroblasts. Macrophages constituted the main immune cell population in the WT (61.29%) and Vsir^-/- groups (77.7%). It should be noted that DCs and fibroblasts were expanded in the Vsir^-/- psoriatic mice. Furthermore, the gene expression signatures were assessed. We observed that Hspb1 and Cebpb were significantly upregulated in the Vsir^-/- psoriatic mice. Differential gene expression and gene ontology enrichment analyses revealed specific gene expression patterns distinguishing these subsets and uncovered putative functions of each cell type. Date analysis resulted in the discovery of a number of novel psoriasis-associated genes in Vsir^-/- mice. Conclusion: We present a comprehensive single-cell landscape of the skin immune cells in Vsir^-/- psoriatic mice. These unprecedented data uncovered the transcriptional landscape and phenotypic heterogeneity of skin macrophages in psoriasis and identified their gene expression signature suggesting specialized functions in Vsir^-/- mice. Our findings will open novel opportunities to investigate the role of VISTA in driving psoriasis.

Keywords: Single-cell RNA-sequencing; VISTA; imiquimod; macrophages; psoriasis.