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Spatial Transcriptomic Analysis of Early and Late Stages of Hidradenitis Suppurativa

ABSTRACT: Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent inflammatory nodules, abscess formation, and sinus tract development. Current biologic therapies provide limited clinical benefit, underscoring the need for deeper understanding of the immune mechanisms driving HS pathogenesis. Objective: We sought to comprehensively characterize the immune landscape of early- and late-stage HS. Methods: Skin biopsies from a total of 15 patients with early and late-stage HS were analyzed using spatial transcriptomics, with 6 samples from these patients further analyzed using single-cell RNA sequencing (scRNA-seq). Gene expression profiles were compared to the epidermal epithelium of acne conglobata in spatial transcriptomics and to psoriasis samples in scRNA-seq as controls. Results: Spatial transcriptomics revealed extensive dermal immune activation from the early stage of HS, including a prominent B-cell signature (immunoglobulins, CD19, MS4A1), neutrophilic infiltration (CD177, MPO, ELANE), and robust IL-23/IL-17 axis, with enriched expression of T17-inducing transcripts (TGFB3, RUNX1, BATF) and T17 cytokines (IL17A, IL17F, IL21). ScRNA-seq confirmed marked plasma cell and B-cell expansion in HS and identified potentially multifunctional B-cells expressing pro-inflammatory cytokines (IL7, IL16) in addition to their role in antigen presentation and antibody production. Furthermore, T-cells were identified as the primary producers of the B-cell chemoattractant CXCL13. Conclusions: HS exhibits early and sustained immune activation characterized by B-cell enrichment, IL-23/IL-17 axis activation, and neutrophilic inflammation extending into the deep dermis. These findings highlight the aggressive nature of HS from its onset, suggesting that early therapeutic targeting of the IL-23/IL-17 axis and B-cell-mediated inflammation may prevent disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294009 | GEO | 2026/02/05

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.

Project description:Background and Purpose:  The chemokine receptor CCR6 is important in guiding pathogenic T17 cells that are implicated in numerous autoimmune diseases including psoriasis to sites of inflammation via the chemokine CCL20. On this basis, pharmacological interventions that inhibit CCR6+ immune cell migration provide a novel therapeutic approach for such diseases. However, the translatability from pre-clinical models to human diseases of such an intervention has so far not been assessed in detail. Here, we evaluate the translatability of a preclinical model of Aldara induced skin inflammation to psoriasis with a particular focus on immune cell trafficking and assess the efficacy of the novel, orally available CCR6 antagonist IDOR-1117-2520 in this model. Experimental Approach:  Here, we evaluated the in vivo therapeutic effects of IDOR-1117-2520, a novel, highly selective, potent, and orally available CCR6 small molecule inhibitor, in the Aldara mouse model of skin inflammation. To understand in detail CCR6 inhibition on the inflammatory response, flow cytometry, RNA sequencing, and transcriptome-based cell type deconvolution approaches were used to characterize immune cell migration patterns and to compare the results to publicly available human psoriasis transcriptomics data. Key Results:  IDOR-1117-2520 dose dependently reduced infiltration of CCR6 + immune cells into inflamed skin and was equally efficacious as IL-17 and IL-23 inhibition in reducing inflammation in the skin. Pathway analysis highlighted the strong molecular similarities in immune response between human psoriasis and the Aldara mouse model. Genes associated with the IL-17/IL-23 pathway were prominently expressed in both human psoriasis and in the mouse model. CCR6 inhibition modulated multiple pathways associated with inflammation beyond the proximal IL-17/IL-23 pathway. A chemokine-chemokine receptor interaction map implicated the CCL20-CCR6 as the dominant axis in recruiting pathogenic T17 cells in this model system, as well as in human psoriasis. Conclusion and Implications:  These results suggest that IDOR-1117-2520 could provide a promising novel targeted therapeutic approach to treating psoriasis and, potentially, other autoimmune diseases with an involvement of CCR6/CCL20 axis and the IL-17/IL-23 pathway. The data provide rationale for the further development of IDOR-1117-2520, which is currently being evaluated in a clinical phase 1 trial (ISRCTN28892128).

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Spatial Transcriptomic Analysis of Early and Late Stages of Hidradenitis Suppurativa

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