AIMS: To elucidate the transcriptomic profile of hyperproliferative keratinocytes in the inflammatory skin disease hidradenitis suppurativa (HS) using single-cell RNA-sequencing.

METHODS: Single-cell RNA-sequencing was performed on sorted CD45- cells from 6 HS lesional and 3 healthy control skin samples. The data was interpreted using Seurat, Monocle3, enrichR and Nichenet packages.

RESULTS: 23 distinct cellular populations were revealed, including keratinocytes, fibroblasts, melanocytes, endothelial cells, pericytes and smooth muscle cells. A keratinocyte population, termed hyperproliferative keratinocytes given its expression of proliferation markers, was significantly enriched in HS lesions compared to healthy controls. These hyperproliferative keratinocytes were the source of a number of differentially expressed genes in HS, including the antimicrobial peptides S100A7, S100A8 and S100A9, and chemokines CXCL1 and CXCL8, many of which lie downstream of IL-17 signalling. Pseudotime trajectory analysis suggest that these hyperproliferative keratinocytes have an altered differentiation program. Intriguingly, Th17-derived ligands promote the expression of multiple proinflammatory markers in HS keratinocytes detailing an important role of this Th17:keratinocyte axis in HS inflammation. These hyperproliferative keratinocytes also demonstrated a dysregulated metabolic profile with an increase in both glycolysis and oxidative phosphorylation pathways.

CONCLUSION: These findings suggest that hyperproliferative keratinocytes play an important role in the pathogenesis of HS. Th17 cells interact with keratinocytes inducing the expression of proinflammatory markers and altering the differentiation program of HS keratinocytes. To our knowledge, this is the first transcriptomic characterisation of hyperproliferative keratinocytes in HS, which may direct future studies.

Single-cell transcriptomic profiling of hyperproliferative keratinocytes in hidradenitis suppurativa

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