1626 Role of BRD4 signaling in the pathogenesis of hidradenitis suppurativa (HS)

HS is characterized by highly inflamed skin areas manifesting malodorous discharge, cribriform scaring, dermal sinus tract formation, and dermal fibrosis. Inhibitors of TNF-α, interleukin-17, interleukin-12/23 and neutrophils activation, offer some relief to HS patients, however, surgical excision of the involved skin is the main option for drug-resistant patients. Lack of appropriate experimental models recapitulating the molecular pathogenesis of HS is the major impediment in mechanism-based drug discovery. We developed HS epithelial cell and tissue culture based models to define the molecular mechanism underlying HS pathobiology. IPA of Human Signal Transduction open arrays using HS (n=8) and normal skin (n=8) demonstrated the activation of bromodomain-4 (BRD4) signaling leading to HS-associated complex inflammation. BRD4 activation was evident from the enhanced acetylation of proteins particularly histones. Hyper-acetylation of specific histone marks such as H3K27ac, H3K9ac, H4K5ac, H4K8ac and H4K12ac was noted, in addition to elevation in transcription of multiple BRD4 target genes. Confocal images showed high nuclear expression of BRD4 in epidermal and dermal epithelial and inflammatory cells including macrophages and neutrophils. Similar to our data from HS epithelial cells, BRD4-overexpressing A431 cells demonstrated that BRD4 directly regulates the NFκB-STAT3 axis. Indeed, we observed the upregulation of several NFκB-STAT3 axis regulated pro-inflammatory cytokines IL6, IL8 IL1β, IL12p70, IL17α and TNFα etc.Ex vivoHS skin cultures treated with BRD4 inhibitor, CPI-0610, effectively reduced the secretion of pro-inflammatory cytokines/chemokines. Similarly, HS epithelial cells in culture treated with BRD4 inhibitor, JQ1, show attenuated transcription of these genes. In summary, our data show a role of BRD4 signaling in HS pathogenesis and BRD4 inhibitors could provide a novel therapeutic strategy for the management of this debilitating disease.