Single cell transcriptional zonation of human psoriasis skin identifies an alternative immunoregulatory axis conducted by skin resident cells

Abstract

Psoriasis is the most common skin disease in adults. Current experimental and clinical evidences suggested the infiltrating immune cells could target local skin cells and thus induce psoriatic phenotype. However, recent studies indicated the existence of a potential feedback signaling loop from local resident skin cells to infiltrating immune cells. Here, we deconstructed the full-thickness human skins of both healthy donors and patients with psoriasis vulgaris at single cell transcriptional level, and further built a neural-network classifier to evaluate the evolutional conservation of skin cell types between mouse and human. Last, we systematically evaluated the intrinsic and intercellular molecular alterations of each cell type between healthy and psoriatic skin. Cross-checking with psoriasis susceptibility gene loci, cell-type based differential expression, and ligand-receptor communication revealed that the resident psoriatic skin cells including mesenchymal and epidermis cell types, which specifically harbored the target genes of psoriasis susceptibility loci, intensively evoked the expression of major histocompatibility complex (MHC) genes, upregulated interferon (INF), tumor necrosis factor (TNF) signalling and increased cytokine gene expression for primarily aiming the neighboring dendritic cells in psoriasis. The comprehensive exploration and pathological observation of psoriasis patient biopsies proposed an uncovered immunoregulatory axis from skin local resident cells to immune cells, thus provided a novel insight for psoriasis treatment. In addition, we published a user-friendly website to exhibit the transcriptional change of each cell type between healthy and psoriatic human skin.

The need to reassess single-cell RNA sequencing datasets: the importance of biological sample processing

“…In conclusion, understanding skin fibroblast heterogeneity is of great relevance not only in skin homeostasis, but also in ageing 11,31 and disease. [32][33][34][35][36] We sincerely hope these reanalyses help further advance the field of single-cell transcriptomics of human skin. Further refinement of fibroblasts subsets and their identity-defining features will provide a fruitful framework for the advancement of knowledge as well as for the development of novel therapeutic approaches in dermatological disease and skin cancer.…”

Challenges and Opportunities for the Translation of Single-Cell RNA Sequencing Technologies to Dermatology

“…Interestingly, it has been observed that lesional differentiated keratinocytes [40], as well as granular keratinocytes and melanocytes [43], showed an increased expression of IFI27. Gao et al observed an increased regulation of apoptosis in epidermal basal cells [80]. These bulk transcriptomic studies await replication by single-cell analysis.…”

“…Cheng et al [43] discovered a CD1C + CD301A + DC population not previously described, and Hughes et al [70] discovered an over-expression of CCL17, CCL22, and IL12B in an IRF4 + DC population. Gao et al and Kim et al use ligand-receptor analysis to show that DCs bind to T-cells, melanocytes, and suprabasal keratinocytes using LILRB1 and LILRB2 [80] and to pericytes, fibroblasts, and basal epidermis using IL36G, WNT5A, and CD58 [81]. Most of these cell types overexpressed either MHC-I or MHC-II [81].…”

Computational exploration of cellular communication in skin from emerging single-cell and spatial transcriptomic data

“…Customized ligand–receptor analyses of scRNA-seq data collected from psoriatic and vitiligo skin have also identified signaling changes specific to diseases. For example, ligand–receptor analysis revealed the regulatory potential from resident epidermal/mesenchymal cells to dendritic cells during psoriasis [ 59 ]. More recently, cell–cell communication analysis of scRNA-seq of human vitiligo revealed that cell type–specific signaling programs and CCR5–CCL5 signaling was critical to effector CD8+ T cell and Treg function in vitiligo, implying the potential role of chemokine circuits in driving lymphocyte localization [ 60 ].…”