Modeling Hidradenitis Suppurativa: linking genetic susceptibility loci to disease pathogenesis

About This Grant

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting ~1–4% of the population, characterized by inflamed nodules, abscesses, and pus-discharging tunnels in the axillary, inguinal, gluteal, and perianal regions. HS profoundly impairs quality of life and is associated with systemic comorbidities such as metabolic syndrome, type 2 diabetes, cardiovascular disease, inflammatory arthritis, inflammatory bowel disease, and depression. Despite its impact, the pathogenesis of HS remains poorly understood, limiting effective treatment options. HS has a strong genetic basis, with heritability estimates as high as 80%. Recent GWAS and meta-analyses have identified KLF5 and SOX9 as risk factors. While their causal roles remain unclear, both genes are closely linked to hair follicle biology, underscoring the central role of this structure in disease. The goal of this proposal is to define the causal roles of HS-associated genes in pathogenesis. Our single- cell RNA-sequence data show increased KLF5 and SOX9 expression in keratinocytes (KCs) from HS lesional skin, with immunohistochemistry confirming higher protein levels in affected hair follicles and tunnels. Whether these increases directly contribute to disease is unknown, a fundamental gap this project aims to address. We will use mouse molecular genetics, lentiviral delivery, human KC bioassays, and RNA sequencing to test the hypothesis that synchronized upregulation of KLF5 and SOX9 in hair follicle KCs drives structural changes that recruit immune cells and sustain HS pathogenesis. Successful completion of this project will advance understanding of how coordinated KLF5 and SOX9 expression in KCs modulates hair follicle biology and promotes inflammation. It may also establish a new preclinical model of HS, enabling exploration of disease pathogenesis, host-microbe interactions, genetic drivers, and novel therapeutic targets.