Single-cell RNA sequencing identifies long non-coding RNAs enriched in psoriatic epidermal subsets

Abstract

Background

Psoriasis is a chronic inflammatory skin disease characterised by disrupted crosstalk between keratinocytes and immune cells, resulting in epidermal dysfunction. Long non-coding RNAs (lncRNAs) regulate gene expression in a cell- or tissue-specific manner, yet their role in psoriatic epidermal dysfunction remains poorly understood.

Objectives

To generate a single-cell atlas of lncRNA expression in healthy and psoriatic epidermis and identify cell state-specific lncRNAs associated with disease.

Methods

Data from Smart-seq2 single-cell RNA sequencing of sorted CD45⁺ and CD45⁻ epidermal cells from healthy controls and lesional/non-lesional psoriatic skin were analysed. Selected lncRNAs were validated by RT-qPCR, single-molecule in situ hybridisation (RNAscope), and immunofluorescence. The regulation of LINC01137 was studied in IL-17A-treated primary keratinocytes and 3D epidermal models, and its function assessed using siRNA-mediated knockdown in keratinocytes.

Results

We identified 1412 epidermal lncRNAs with robust expression across distinct keratinocyte and immune cell states. LncRNAs exhibited strong cell type-specific expression in both keratinocytes and immune cells, moreover, several lncRNAs showed selective expression in psoriasis-associated cell states. LINC01137 was enriched in activated keratinocytes, induced by IL-17A and correlated with TGF-β pathway activity; its knockdown in primary keratinocytes attenuated TGF-β-induced SERPINE1/PAI-1 expression. LINC00892 was enriched in lesional Th1, Th17 and proliferating CD8⁺ T cells and showed increased expression as well as co-localisation with the T cell marker CD3 in psoriasis epidermis.

Conclusions

This study identifies the single-cell non-coding transcriptomic landscape of the psoriatic epidermis and highlights distinct lncRNA signatures in keratinocytes and immune cells, suggesting their involvement in pathogenic processes in psoriasis.