Stress signalling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa

Abstract

Background The 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 a 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 lesional and perilesional epidermis isolated from HS patients by RNA sequencing (RNA Seq).Methods Pairwise-matched lesional and perilesional HS skin samples of five different donors were obtained and epidermal keratinocytes freshly isolated and processed for RNA extraction and RNA seq. Lesionally regulated genes were analysed by large-scale promoter analysis and functional annotation clustering to identify epidermally overrepresented transcription factor binding sites and functionally related gene groups. Results were experimentally validated with independent epidermal isolates of patient-matched lesional and perilesional HS skin employing qRT-PCR, cell culture, immunoblot and immunostaining. ResultsWe show that HS is characterized by a strong epidermal stress state evident by a significant overrepresentation of an AP-1-driven gene signature and a substantial activation of the stress-activated cJun N-terminal kinase (JNK) pathway in lesional epidermis. Additionally, our data reveal a strong induction of STAT1 activation in lesional HS epidermis that likely results from IFNc production and triggered expression of key inflammatory genes coordinating innate immune activation and the adaptive T-cell response in HS. Conclusions Our data implicate a key role of stress signalling and JAK/STAT1 activation in disease progression of HS and suggest interference with JAK/STAT1 signalling as a potentially promising therapeutic approach for HS.

Emerging Treatments and the Clinical Trial Landscape for Hidradenitis Suppurativa Part I: Topical and Systemic Medical Therapies

“…They participate in the JAK–signal transducer and activator of transcription (STAT) pathway, which regulates multiple inflammatory signals, including interleukin (IL)-1b, IL-6, IL-17, IL-23, interferons (IFNs), and tumor necrosis factor (TNF)-α [ 7 , 8 ]. JAK3 gene transcripts as well as STAT1, STAT4, and STAT5 promoter binding sites are elevated in HS lesional skin [ 9 , 10 ]. IFN-induced STAT1 activation was suppressed in vitro by JAK1-selective inhibition by upadacitinib [ 9 ].…”

“…JAK3 gene transcripts as well as STAT1, STAT4, and STAT5 promoter binding sites are elevated in HS lesional skin [ 9 , 10 ]. IFN-induced STAT1 activation was suppressed in vitro by JAK1-selective inhibition by upadacitinib [ 9 ].…”

Causal association between inflammatory bowel disease and hidradenitis suppurativa: A two-sample bidirectional Mendelian randomization study

“…Tofacitinib, a pan-JAK inhibitor, had distinct efficacy in UC and CD patients, indicating that the JAK/STAT pathway was activated differently in each group of patients ( 44 , 45 ). STAT1 signaling in T cells was elevated in CD but not in UC, and STAT1 mRNA was elevated in HS patients ( 46 , 47 ). This shows that STAT1 may function as a mediator between UC, CD, and HS.…”

Tissue comparability and bias in hidradenitis suppurativa transcriptomic studies

“…A recent study published in PNAS deployed a series of HS transcriptomic studies to prioritize cells and pathways for therapeutic intervention ( 1 ). They identify a keratinocyte population in HS lesions with a molecular signature that has been well reported in HS, including S100A7/8/9, KRT6 ( 2 , 3 ). Using statistical modeling, they conclude that this population of cells incites disease by recruiting immune cells into the skin.…”