The role of cortisol synthesis in pathogenesis of Hidradenitis suppurativa tunnels

Abstract Hidradenitis suppurativa (HS) is a common, debilitating inflammatory disease characterized by unique pathological features that includes epithelialized tunnel formation. Chronically draining, intradermal tunnels are unique feature of HS pathology and contribute to robust inflammation significantly affecting patients’ quality of life. Tragically, no consistently effective treatments exist for HS tunnels. In addition, the progress in the field is hampered by the lack of clinically relevant HS models. We assembled a multidisciplinary collaborative team with unique and complementary expertise in HS, 3D skin models, glucocorticoid synthesis and signaling. The team generated preliminary data obtained from patients’ tissue specimens: samples from HS tunnel, lesional skin above the tunnel, along with the age, gender, and location-matched healthy skin controls and found that cortisol and steroid synthesis pathways are markedly suppressed in HS tunnels, leading to perpetual pro- inflammatory keratinocyte activation. We also found lack of glucocorticoid receptor (GR) activation in HS tunnels, which was supported by HS transcriptomics signature characterized by marked downregulation of cortisol synthesis and GR signaling, again uniquely associated with the tunnels and not observed in lesional keratinocytes. Importantly, we successfully developed the first 3D organotypic model from primary HS tunnel keratinocytes and fibroblast that recapitulates tunnels structure in patients. Based on the robust preliminary and published data, we propose a novel concept of HS tunnel as an intradermal perpetual cellular activation process, in which its deregulation, in particular lack of cortisol synthesis, is a major contributor to pathophysiology. Further, we hypothesize that inhibition of epidermal and dermal cortisol production coupled with dysfunctional cellular activation play a central role in HS tunnel pathogenesis. To test this, we outlined three Aims which will utilize a) tissue and b) primary cell obtained from HS patients in distinct locations: HS tunnels, skin above the tunnel, perilesional skin (all from the same patient) and location, age, sex, ethnicity matched controls; c) organotypic 3D HS tissue generated from these primary cells. HS tissue, cells and organotypic cultures will be maintained under normoxia and hypoxic conditions and challenged by insult and Aim 1 will determine the role of cortisol synthesis in HS tunnels and 3D organoids by using spatial transcriptomics and measuring cortisol production, whereas the other two Aims will offer mechanistic insights that can reveal potential new therapeutic avenues. Aim 2 will test if targeting cortisol synthesis can restore the function of tunnel keratinocytes and fibroblasts and their activation, whereas Aim 3 will focus on how genomic and non-genomic GR signaling contributes to pathophysiology of HS tunnels and HS in general. Better understanding the mechanisms through which cortisol synthesis and GR signaling modulate tunnel biology and inflammatory response in HS will offer mechanistic insights regarding HS pathophysiology and may lead to novel tunnel-targeted therapeutics to modulate cortisol synthesis in HS and ameliorate disease progression.