The skin transcriptome in hidradenitis suppurativa uncovers an antimicrobial and sweat gland gene signature which has distinct overlap with wounded skin

Abstract

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease resulting in non-healing wounds affecting body areas of high hair follicle and sweat gland density. The pathogenesis of HS is not well understood but appears to involve dysbiosis-driven aberrant activation of the innate immune system leading to excessive inflammation. Marked dysregulation of antimicrobial peptides and proteins (AMPs) in HS is observed, which may contribute to this sustained inflammation. Here, we analyzed HS skin transcriptomes from previously published studies and integrated these findings through a comparative analysis with a published wound healing data set and with immunofluorescence and qPCR analysis from new HS patient samples. Among the top differently expressed genes between lesional and non-lesional HS skin were members of the S100 family as well as dermcidin , the latter known as a sweat gland-associated AMP and one of the most downregulated genes in HS lesions. Interestingly, many genes associated with sweat gland function, such as secretoglobins and aquaporin 5 , were decreased in HS lesional skin and we discovered that these genes demonstrated opposite expression profiles in healing skin. Conversely, HS lesional and wounded skin shared a common gene signature including genes encoding for S100 proteins, defensins, and genes encoding antiviral proteins. Overall, our results suggest that the pathogenesis of HS may be driven by changes in AMP expression and altered sweat gland function, and may share a similar pathology with chronic wounds.

Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa

“…It is important to note that our study is the first to our knowledge to focus on a clinically homogenous group of patients with Hurley stage I. This might explain differences with previous studies, which involved patients with variable and often severe HS lesions ( 10 , 12 , 14 , 15 ). Our immune profiling of PBMCs from patients with HS highlighted higher frequencies of NK cells expressing granzyme B and perforin and producing IFN-γ upon stimulation ( Supplemental Figure 2, B–D ).…”

Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa

“…At the skin level, they reported an abundance of immunoglobulins, antimicrobial peptides, an interferon signature and complement system dysregulation with involvement of S100A7 , S100A8 , S100A9 , DEFB4 and SERPINB3 . Coates et al . have compared the HS microarray data set of Block et al ., with a transcriptional signature of biopsy‐induced wounds of the human skin and the oral mucosa published by Iglesias‐Bartolome et al .…”

“…At the skin level, they reported an abundance of immunoglobulins, antimicrobial peptides, an interferon signature and complement system dysregulation with involvement of S100A7, S100A8, S100A9, DEFB4 and SERPINB3. Coates et al 72 have compared the HS microarray data set of Block et al, 18 with a transcriptional signature of biopsy-induced wounds of the human skin and the oral mucosa published by Iglesias-Bartolome et al 73 and suggested that the pathogenesis of HS may be driven by changes in antimicrobial peptide expression and altered sweat gland function and may share a similar pathology with chronic wounds. In our study, in addition to studying the molecular taxonomy, we confirmed this dysregulation and further characterized it systematically at the protein and cellular level via immunohistochemistry.…”

Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa

“…The role of sweat glands in this disease also remains unclear. Although the intertriginous areas are rich in apocrine glands (Hoffman et al, 2017;Vossen et al, 2018), eccrine gland transcriptomic signatures are also dysregulated in HS (Coates et al, 2019). Additional dermal factors, such as aberrant fibroblast responses, may contribute to the inflammatory sequelae of HS (Frew et al, 2019), including dermal tunnels, persistent suppuration, fibrosis, and systemic inflammation.…”