Abstract
ABSTRACTBackgroundThe underlying pathogenetic factors generating the innate immune signal necessary for T cell activation, initiation and chronification of Hidradenitis suppurativa (HS, also known as Acne inversa) are still poorly understood. Emerging evidence suggests that defective keratinocyte function critically contributes to HS disease development and progression.ObjectivesTo elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of isolated lesional and perilesional HS epidermis by RNA sequencing.MethodsLesional and perilesional HS skin samples of at least 3 different donors were obtained. Isolated epidermal keratinocytes were further processed for cell culture, protein extraction, immunostaining procedures or RNA isolation and RNA sequencing. For large scale promotor site analysis, DEGs were analyzed for overrepresented transcription factor binding sites. Functional annotation clustering for analyzing enriched functional-related gene groups was performed employing the DAVID Bioinformatics Resources.ResultsWe show that HS is characterized by a strong epidermal stress state as evident by a significant overrepresentation of an AP-1-driven stress signature in the overall gene expression pattern of lesional keratinocytes and a substantial activation of the stress-activated cJun N-terminal kinase (JNK) pathway in lesional HS epidermis. Additionally, our data reveal a strong induction of STAT1 activation in lesional HS epidermis that likely results from IFNγ production and governs the expression of key inflammatory genes that coordinate activation of innate immunity and the adaptive T cell response in HS.ConclusionsTaken together, these data implicate a new role of combined stress signaling and JAK/STAT1 pathway activation in disease progression of HS suggesting interference with JAK/STAT1 signaling as a potentially promising therapeutic approach for HS.
Publisher
Cold Spring Harbor Laboratory