Research Background

Current Status and Challenges in Hidradenitis Suppurativa Research

Hidradenitis Suppurativa (HS) is a relatively common and highly morbid inflammatory skin disease. It affects approximately 1% of the global population, disproportionately impacting women and marginalized groups. HS’s pathogenesis is complex, involving genetic, immune, endocrine, and environmental factors, with specific risk factors including obesity, smoking, and family history.

The hallmark of HS is the formation of cysts and fibrosis in affected areas, significantly impacting patients’ quality of life and leading to various comorbidities such as inflammatory bowel diseases and psychological disorders. Additionally, HS patients have a higher 5-year mortality rate compared to those with other inflammatory skin diseases. Although biologic therapies targeting specific cytokines, like TNF-α inhibitors (e.g., adalimumab), have been approved for HS treatment, these treatments vary in efficacy among individuals, and some patients experience worsening symptoms or new complications. This highlights the need for more effective therapeutic strategies.

Motivation and Objectives

Due to the historical scarcity of accurate ex vivo models and animal models that can faithfully replicate HS pathology, researchers have struggled to fully understand the disease mechanisms and develop effective treatments. Therefore, this study aims to develop a standardized whole-tissue explant model to investigate HS pathogenesis and evaluate the efficacy of potential treatments. By using this model, researchers can better identify key cytokines involved in HS and assess the effectiveness of different therapeutic approaches.

Paper Source

This paper was co-authored by researchers from multiple institutions, including the University of California, San Francisco (UCSF), and published in Experimental Dermatology in 2025. The lead authors include Phoebe E. Leboit, Dhara U. Patel, Jarish N. Cohen, et al.

Research Methods and Procedures

Sample Collection and Processing

Researchers collected 20 HS lesion samples and 23 healthy control samples. All samples were stored at 4°C and processed within 48 hours. To ensure consistency, all skin samples were dermatomed to a uniform thickness of 800 micrometers and prepared into standard-sized biopsy samples using a punch tool. These samples were then placed in a 12-well plate containing agar-infused media for 24-hour culture.

Experimental Design and Analysis

1. Establishment of the Biopsy Model

Microscopic observations revealed that after 24 hours of culture, HS biopsy samples showed decreased perivascular and interstitial lymphocytic infiltrates, along with keratinocyte necrosis in the upper epidermis and eccrine secretory glands. Similar keratinocyte necrosis was observed in healthy control samples, likely due to ischemic changes. Enzymatic digestion of the samples produced an average of 1.43 million cells, with 65% viability. Quantitative PCR analysis indicated good retention of immune cell populations, as evidenced by the expression levels of PTPRC (CD45) and CD3E.

2. Drug Penetration Testing

To verify the penetration of small molecules through the tissue, researchers used CPD A, a fluorescent small molecule. Results showed that drug exposure began by 4 hours and saturated the tissue by 24 hours. This indicated that a 24-hour incubation period maximized drug delivery while minimizing cell loss.

3. Cytokine Concentration Analysis

The researchers measured the expression of IL-6, IL-8, GM-CSF, IFN-γ, IL-1β, TNF-α, IL-17A, and IL-23A at both RNA and protein levels. Baseline results showed significantly higher IL-17A protein concentrations in HS samples compared to healthy controls. During culture, IL-6 and IL-8 increased in both RNA and protein levels in both sample types but were more pronounced in HS samples. TNF-α, IL-1β, and IL-17A also showed significant increases in HS samples but not in healthy controls.

4. Single-Cell Suspension Culture Analysis

Comparisons between HS and healthy skin samples in single-cell suspension cultures revealed higher concentrations of IL-8 and IL-6 in both types, with significantly higher IL-8 levels in HS samples. Additionally, TNF-α and IL-17A protein concentrations were significantly elevated in HS samples.

5. Evaluation of Treatment Effects

The effects of dexamethasone and IL-2 on HS biopsy samples were further tested. Dexamethasone significantly reduced the transcription levels of IL-6, CXCL8, IL-1β, CSF2, and IL-23, as well as the protein concentrations of IL-1β, CXCL1, CCL3, and PDGF-AA. IL-2 significantly increased CD25 expression in CD4 and effector T cells and raised the proportion of regulatory T cells.

Key Findings

Cytokine Expression Patterns

The study found that IL-6 and IL-8 expression increased across all samples, possibly related to tissue damage responses. In contrast, IL-1β, TNF-α, and IL-17A showed significant increases specifically in HS samples, indicating their close association with HS inflammation. High correlations between certain cytokines, such as IL-1β with TNF-α and IL-17A, suggested potential synergistic interactions.

Application Value of the Model

The researchers noted that this standardized whole-tissue explant model can be used not only to study HS pathogenesis but also to evaluate the effects of different treatments. Compared to traditional single-cell suspension cultures, this model better preserves tissue structure and allows for microscopic observation of cell-cell interactions.

Conclusion and Implications

Scientific Value and Future Applications

This study developed a standardized whole-tissue explant model that successfully mimics HS pathology and identifies key cytokines involved in HS. The findings provide crucial insights into HS pathogenesis and lay the foundation for developing more effective treatments. Moreover, this model can be used to evaluate novel drugs, accelerating clinical translation research.

Highlights

1. Innovativeness: First established a standardized whole-tissue explant model capable of replicating HS pathology ex vivo.
2. Comprehensiveness: Analyzed changes in multiple cytokines at both RNA and protein levels, revealing critical inflammatory mediators in HS.
3. Practicality: The model can be used to study HS pathogenesis and evaluate treatment efficacy, offering significant practical value.

Limitations and Future Directions

Despite its success in modeling HS pathology, the model has limitations. For example, the inflammatory state may be influenced by sample processing, and healthy control samples cannot fully match HS samples in terms of age, sex, and sampling site. Future research should aim to optimize the model design to enhance sample consistency and comparability for better clinical application.

This study provides important tools and technical support for HS pathogenesis research and the development of new therapeutic strategies, potentially advancing the field further.