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Epigenetic Switch Reshapes Epithelial Stem/Progenitor Cells Signatures and Contributes to Inflammatory Programming in Hidradenitis Suppurativa [scRNA-seq]

ABSTRACT: In this study, we used single-cell RNA-sequencing to reveal how cellular heterogeneity of Hidradenitis Suppurativa (HS) lesional epidermis was reshaped at the transcriptional level. By comparison with healthy interfollicular epidermal basal cells, in HS we revealed marked gene signatures centered on mitotic chromosome segregation, DNA replication and repair as well as cell-cell adhesion and chromatic remodeling. Combing the pseudotime-ordered single-cell trajectory with the spatial localization analysis of defined basal cells, we further identified and validated a global alteration in cellular diversity within HS epidermis characterized by basal I-III cells hyperproliferation, concomitant decreases in superbasal keratinocytes, and phenotypic shifts toward the S100A cluster highly expressing pro-inflammatory genes S100A7/8/9. Cell-cell communication modeling suggested that HS BIII keratinocytes and S100A population serve as a crucial source to trigger IL-1 and IL-10 inflammatory cascades in the disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226427 | GEO | 2023/10/18

REPOSITORIES: GEO

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Project description:Background: Based on the mounting evidence that Type 17 T-cells (T17 cells) and increased IL-17 play a key role in driving hidradenitis suppurativa (HS) lesion development, biologics previously used in psoriasis that block signaling of IL-17A and/or IL-17F isoforms have been repurposed to treat HS. Objective: Our aim was to characterize the transcriptome of HS T17 cells compared to the transcriptome of psoriasis T17 cells, and their ligand-receptor interactions with neighborhood immune cell subsets. Methods: Single-cell data of 12,300 cutaneous immune cells from 8 de-roofing surgical HS skin samples that included dermal tunnels were compared with single-cell data of psoriasis skin (19,525 cells from 11 samples) and control skin (11,920 cells from 10 samples). All the single-cell data were generated by the identical protocol. Results: HS T17 cells expressed lower levels of IL23R and higher levels of IL1R1 and IL17F compared to psoriasis T17 cells (p < 0.05). HS regulatory T-cells (Tregs) expressed higher levels of IL1R1 and IL17F compared to psoriasis Tregs (p < 0.05). Semimature dendritic cells (DCs) were the major immune cell subsets expressing IL1B in HS, and IL-1B ligand-receptor interactions between semimature DCs and T17 cells were increased in HS compared to psoriasis (p < 0.05). HS dermal tunnel keratinocytes (KCs) expressed inflammatory cytokines (IL17C, IL1A, IL1B, and IL6) different from HS epidermis KCs (IL36G) (p < 0.05). 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 paracrine IL-1/IL-6 loop. Conclusion: The IL-1B-T17 cell cytokine axis is likely a dominant pathway in HS with HS T17 cells activated by IL-1B signaling, unlike psoriasis T17 cells which are activated by IL-23 signaling. Clinical Implication: Biologics targeting IL-17 isoforms and IL-1B may be effective for HS but biologics targeting IL-23 may be less effective for HS.

Dataset Information

Epigenetic Switch Reshapes Epithelial Stem/Progenitor Cells Signatures and Contributes to Inflammatory Programming in Hidradenitis Suppurativa [scRNA-seq]

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