RT Journal Article SR Electronic T1 Stress signaling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa JF medRxiv FD Cold Spring Harbor Laboratory Press SP 2021.09.24.21263813 DO 10.1101/2021.09.24.21263813 A1 Frings, VG A1 Jopp, L A1 Srivastava, M A1 Presser, D A1 Goebeler, M A1 Schmidt, M YR 2021 UL http://medrxiv.org/content/early/2021/09/27/2021.09.24.21263813.abstract AB Background The 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.Objectives To elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of isolated lesional and perilesional HS epidermis by RNA sequencing.Methods Lesional 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.Results We 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.Conclusions Taken 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.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by the Interdisziplinaeres Zentrum fuer Klinische Forschung (IZKF), University Hospital Wuerzburg, Germany (ZZ/25).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:ethical vote was given by the local Ethics Committee, University of Wuerzburg, Bavaria, Germany; No. 306/12All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesDatasets related to this article can be found under EGA ID EGAS00001005544, hosted at EGA European Genome-Phenome Archive (https://ega-archive.org).