Single-cell transcriptomics suggest distinct upstream drivers of IL-17A/F in hidradenitis versus psoriasis

Abstract

Background: On the basis of the mounting evidence that type 17 T (T17) cells and increased IL-17 play a key role in driving hidradenitis suppurativa (HS) lesion development, biologic agents used previously in psoriasis that block signaling of IL-17A and/or IL-17F isoforms have been repurposed to treat HS.

Objective: Our research aimed to characterize the transcriptome of HS T17 cells compared to the transcriptome of psoriasis T17 cells, along with their ligand-receptor interactions with neighborhood immune cell subsets.

Methods: Single-cell data of 12,300 cutaneous immune cells from 8 deroofing surgical HS skin samples including dermal tunnels were compared to single-cell data of psoriasis skin (19,525 cells from 11 samples) and control skin (11,920 cells from 10 samples). All single-cell data were generated by the same protocol.

Results: HS T17 cells expressed lower levels of IL23R and higher levels of IL1R1 and IL17F compared to psoriasis T17 cells (P < .05). HS Treg cells expressed higher levels of IL1R1 and IL17F compared to psoriasis Treg cells (P < .05). Semimature dendritic cells were the major immune cell subsets expressing IL1B in HS, and IL-1β ligand-receptor interactions between semimature dendritic cells and T17 cells were increased in HS compared to psoriasis (P < .05). HS dermal tunnel keratinocytes expressed inflammatory cytokines (IL17C, IL1A, IL1B, and IL6) that differed from the HS epidermis keratinocytes (IL36G) (P < .05). IL6, which synergizes with IL1B to maintain cytokine expression in T17 cells, was mainly expressed by fibroblasts in HS, which also expressed IL11⁺ inflammatory fibroblast genes (IL11, IL24, IL6, and POSTN) involved in the paracrine IL-1/IL-6 loop.

Conclusion: The IL-1β-T17 cell cytokine axis is likely a dominant pathway in HS with HS T17 cells activated by IL-1β signaling, unlike psoriasis T17 cells, which are activated by IL-23 signaling.

Keywords: Hidradenitis suppurativa; IL-1; IL-17A; IL-17F; IL-1R1; IL-23; T cell; dendritic cell; fibroblast; keratinocyte; psoriasis; single-cell RNA sequencing; type 17 T cells.