Abstract
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent abscesses, nodules, and sinus tracts in areas of high hair follicle and sweat gland density. These sinus tracts can present with purulent drainage and scar formation. Dysregulation of multiple immune pathways drives the complexity of HS pathogenesis and may account for the heterogeneity of treatment response in HS patients. Using transcriptomic approaches, including single-cell sequencing and protein analysis, we here characterize the innate inflammatory landscape of HS lesions. We identified a shared upregulation of genes involved in interferon (IFN) and antimicrobial defense signaling through transcriptomic overlap analysis of differentially expressed genes (DEGs) in datasets from HS skin, diabetic foot ulcers (DFUs), and the inflammatory stage of normal healing wounds. Overlap analysis between HS- and DFU-specific DEGs revealed an enrichment of gene signatures associated with monocyte/macrophage functions. Single-cell RNA sequencing further revealed monocytes/macrophages with polarization toward a pro-inflammatory M1-like phenotype and increased effector function, including antiviral immunity, phagocytosis, respiratory burst, and antibody-dependent cellular cytotoxicity. Specifically, we identified the STAT1/IFN-signaling axis and the associated IFN-stimulated genes as central players in monocyte/macrophage dysregulation. Our data indicate that monocytes/macrophages are a potential pivotal player in HS pathogenesis and their pathways may serve as therapeutic targets and biomarkers in HS treatment.
Highlights
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a relapsing and remitting course
While this transcriptomic analysis showed that interferon stimulated genes (ISGs) were elevated in HS lesions as well as in the inflammatory phase of healing wounded skin, we did not address how such an immune response may relate to a chronic wound environment [16]
We found that many differentially expressed gene (DEG) involved in IFN pathways were upregulated among all three datasets, including IRF7, ISG15, ISG20, and OASL (Figure 1A)
Summary
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a relapsing and remitting course. Severe features of HS disease may include sinus tracts, malodorous discharge, and extensive scarring in affected skin areas [1]. These debilitating features can cause substantial psychosocial burden, increasing the risk of mood disorders and completed suicide [2, 3]. An interplay of multiple environmental factors, genetics, host-microbe interactions, and immune dysregulation likely contribute to disease risk and severity [1]. Tumor necrosis factor (TNF)-α, interleukin (IL)1β, IL-12, IL-17, IL-23, and complement have been identified as relevant targets for immunotherapy in patients with HS [4,5,6,7,8]
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