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. 2023 Sep;152(3):656-666.
doi: 10.1016/j.jaci.2023.05.012. Epub 2023 Jun 2.

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

Jaehwan Kim  1 , Jongmi Lee  2 , Xuan Li  3 , Hyun Soo Lee  3 , Katherine Kim  2 , Vasuma Chaparala  2 , William Murphy  4 , Wei Zhou  5 , Junyue Cao  5 , Michelle A Lowes  3 , James G Krueger  6
Affiliations

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

Jaehwan Kim et al. J Allergy Clin Immunol. 2023 Sep.

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.

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Conflict of interest statement

J.K. was supported by NIAMS K23 Career Development Award (K23AR080043). J.K. has received research support from Novartis and AbbVie. MAL has served on the advisory boards for Abbvie, InflaRx, Janssen, and UCB, Viela Bio, and consulted for Almirall, BSN medical, Incyte, Janssen, Kymera, Phoenicis, and XBiotech. MAL is on the medical board of the Hidradenitis Suppurativa Foundation. J.G.K. has received research support from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. The rest of the authors declare that they have no relevant conflict of interest.

Figures

Figure 1.
Figure 1.
T17 cell gene expression comparison between HS and psoriasis. A, IL17A, IL17F, and IL23R expression comparison between HS, psoriasis, and control in total immune cells (*p < 0.05). B, The average gene expression of T17 cells and non-T17 T-cells, split by HS, psoriasis, and control. C, The average gene expression of HS T17 cells, split by IL17A or IL17F expression. IL17A (red), IL17F (green), and IL17A and IL17F coexpression (yellow) within the T-cell subset clusters visualized in low-dimensional space. D, Volcano plot displaying differentially expressed genes of IL17F+ T17 cells between HS and psoriasis (vertical dotted line = fold change of 1.2, horizontal dotted line = p-value of 0.05).
Figure 2.
Figure 2.
Treg gene expression comparison between HS, psoriasis, and control. A, The average gene expression of the Treg cluster, split by HS, psoriasis, and control. B, Volcano plot displaying differentially expressed genes of Tregs between HS and psoriasis (vertical dotted line = fold change of 1.2, horizontal dotted line = p-value of 0.05). C, The average gene expression of HS Tregs, split by Tregs with IL17A/F expression vs. Tregs without IL17A/F expression.
Figure 3.
Figure 3.
DC gene expression comparison between HS, psoriasis, and control. A, IL1B expression comparison between HS, psoriasis, and control in total immune cells (*p < 0.05) and immune cell subset clusters (violin plot). B, The average gene expression of the mature and semimature DC clusters, split by HS, psoriasis, and control. C, Volcano plot displaying differentially expressed genes of semimature DCs between HS and psoriasis (vertical dotted line = fold change of 1.2, horizontal dotted line = p-value of 0.05).
Figure 4.
Figure 4.
Keratinocyte gene expression comparison between HS, psoriasis, and control. A, IL36G and IL1RL1(ST2) expression comparison between HS epidermis, HS dermal tunnel, psoriasis, and control in immune cell subset clusters (violin plot). B, The average gene expression of the keratinocyte clusters, split by HS dermal tunnel, HS epidermis, psoriasis, and control. C, D, Volcano plots displaying differentially expressed genes of keratinocytes between (C) HS dermal tunnel and psoriasis and (D) HS dermal tunnel and HS epidermis (vertical dotted line = fold change of 1.2, horizontal dotted line = p-value of 0.05).
Figure 5.
Figure 5.
Fibroblast gene expression comparison between HS, psoriasis, and control. A, IL11, IL24, IL6, and POSTN expression comparison between HS, psoriasis, and control in immune cell subset clusters (violin plot). B, The average gene expression of the fibroblast cluster, split by HS, psoriasis, and control. C, Volcano plot displaying differentially expressed genes of fibroblasts between HS and psoriasis (vertical dotted line = fold change of 1.2, horizontal dotted line = p-value of 0.05).
Figure 6.
Figure 6.
Top 10 ligand-receptor interactions of IL-17F, IL-1B, IL-6, and IL-33 that are increased in HS compared to psoriasis
See this image and copyright information in PMC

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