Distinct IL‑17A and retinoic acid–associated gene programs are enriched in epithelialized tunnels in severe hidradenitis suppurativa.

We used spatial transcriptomics to show that severe HS tunnel epithelium have a conserved transcriptional program different from that of the overlying epidermis. Pathway and differential gene intersection analyses demonstrated that IL-17A signaling is the dominant cytokine-associated driver of tunnel inflammation, whereas TNFa signaling showed minimal overlap with the tunnel signature.

Unexpectedly, transcription factor enrichment and gene set enrichment analyses identified dysregulated retinoic acid (RA)-associated signaling in tunnels. Functional studies in primary keratinocytes revealed that IL-17A upregulated a subset of RA-associated tunnel genes through a mechanism independent of retinoic acid receptor (RAR) signaling. Another distinct subset of tunnel-associated genes, including mucosal keratins such as KRT13, was not induced by IL-17A but instead required RAR signaling for their expression.