Single-cell and spatial transcriptomics reveal elevated pro-inflammatory fibroblasts and hormonal activity in hidradenitis suppurativa

Summary: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful nodules, abscesses, and draining tunnels. While immune dysfunction and follicular occlusion are central to HS pathogenesis, dysregulated fibroblast activity may contribute to fibrosis and tunnel formation. Fibroblasts play a key role in tissue repair and exhibit heterogeneity in multiple fibrotic skin diseases, which are often characterized by fibroblast hyperproliferation and excessive extracellular matrix accumulation. However, fibroblast heterogeneity in HS is not fully characterized and the role of fibroblasts in disease progression remains of interest. In this study, we explored fibroblast heterogeneity in HS by performing single-cell RNA seq and spatial transcriptomics on skin samples from HS nodules, perilesional skin and normal skin. Our results identify five HS fibroblast subpopulations: secretory-papillary, secretory-reticular, mesenchymal, pro-inflammatory and myofibroblasts. A population of pro-inflammatory fibroblasts expressing inflammatory cytokines and other markers of immune activity was uniquely present in HS nodules but absent in perilesional and normal skin. Importantly, genes encoding hormone receptors, including those for androgen, glucocorticoid, estrogen, progesterone, thyroid, and growth hormone, were more highly expressed in HS nodule fibroblasts, as compared to fibroblasts from normal skin. While the involvement of hormones in HS pathogenesis is undefined, the disease's onset after puberty, flare-ups during menstruation and pregnancy, and the effectiveness of hormonal therapies in treating some HS patients strongly suggest a link between sex hormones and immune activity in HS. Our findings offer new insight into the inflammatory and hormonal activity of HS fibroblasts and their potential role in disease progression. Targeting fibroblast-driven inflammation and hormonal signaling may offer new therapeutic approaches for HS treatment. Arthy Suresh¹, Henry Hsia², Anna Eisenstein¹ 1. Dept. of Dermatology, Yale School of Medicine, New Haven, CT, United States. 2. Dept. of Plastic and Reconstructive Surgery, Yale School of Medicine, New Haven, CT, United States. Adaptive and Auto-Immunity