Skin microbiome dysbiosis drives pathogenesis in murine models of hidradenitis suppurativa

Summary: Hidradenitis suppurativa (HS) is a chronic inflammatory dermatosis with a complex pathogenesis influenced by both genetic and environmental factors, many of which remain poorly understood. Mutations in <i>Ncstn</i>, frequently observed in familial HS, disrupt Notch signaling- a pathway which is critical for maintaining skin homeostasis. To address the limitations of existing <i>in vivo</i> models, we developed two novel murine systems: keratin 17-driven <i>Ncstn</i> knockout (NEKO) mice and keratin 17-expressing tissue <i>Rbpj</i> knockout (REKO) mice. Both models recapitulated key HS phenotypes, including epidermal hyperplasia, follicular occlusion, and inflammatory cell infiltration. Histological analysis revealed a cellular infiltrate resembling human HS lesions, characterized by macrophages, IL-17⁺ T lymphocytes, and neutrophils. Given the emerging role of microbial dysbiosis in inflammatory skin conditions, we performed 16S rRNA gene sequencing on the skin microbiomes of these murine models. The analysis revealed significant dysbiosis in both models, with a marked enrichment of <i>Corynebacterium mastitidis</i>. Subsequent antibiotic treatment reduced cutaneous inflammation in both NEKO and <i>REKO </i>mice, suggesting that <i>C. mastitidis</i> and associated dysbiosis may drive HS pathogenesis. The phenotypic similarities between the <i>NEKO and REKO </i>models further suggest that <i>Rbpj</i> dysregulation likely operates downstream of <i>Ncstn</i> loss within the Notch signaling cascade. These findings underscore the pivotal roles of <i>Ncstn</i> and <i>Rbpj</i> in HS pathogenesis and highlight the skin microbiome as a promising therapeutic target. Further studies are needed to elucidate the precise mechanisms by which <i>C. mastitidis</i> contributes to HS inflammation in these murine models. Yuqian Chang¹, Zhenpeng Dai¹ 1. Columbia University, New York, NY, United States. Innate Immunity, Microbiology, and Microbiome