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

Abstract

Background The large unmet need of hidradenitis suppurativa/acne inversa (HS) therapy requires the elucidation of disease‐driving mechanisms and tissue targeting. Objective Robust characterization of the underlying HS mechanisms and detection of the involved skin compartments. Methods Hidradenitis suppurativa/acne inversa molecular taxonomy and key signalling pathways were studied by whole transcriptome profiling. Dysregulated genes were detected by comparing lesional and non‐lesional skin obtained from female HS patients and matched healthy controls using the Agilent array platform. The differential gene expression was confirmed by quantitative real‐time PCR and targeted protein characterization via immunohistochemistry in another set of female patients. HS‐involved skin compartments were also recognized by immunohistochemistry. Results Alterations to key regulatory pathways involving glucocorticoid receptor, atherosclerosis, HIF1α and IL17A signalling as well as inhibition of matrix metalloproteases were detected. From a functional standpoint, cellular assembly, maintenance and movement, haematological system development and function, immune cell trafficking and antimicrobial response were key processes probably being affected in HS. Sixteen genes were found to characterize HS from a molecular standpoint (DEFB4, MMP1, GJB2, PI3, KRT16, MMP9, SERPINB4, SERPINB3, SPRR3, S100A8, S100A9, S100A12, S100A7A (15), KRT6A, TCN1, TMPRSS11D). Among the proteins strongly expressed in HS, calgranulin‐A, calgranulin‐B and serpin‐B4 were detected in the hair root sheath, koebnerisin and connexin‐32 in stratum granulosum, transcobalamin‐1 in stratum spinosum/hair root sheath, small prolin‐rich protein‐3 in apocrine sweat gland ducts/sebaceous glands‐ducts and matrix metallopeptidase‐9 in resident monocytes. Conclusion Our findings highlight a panel of immune‐related drivers in HS, which influence innate immunity and cell differentiation in follicular and epidermal keratinocytes as well as skin glands.

Hidradenitis suppurativa is an autoinflammatory keratinization disease: A review of the clinical, histologic, and molecular evidence

“…The inflammatory signature of established hidradenitis suppurativa has been well characterized in multiple histologic 26,41 and molecular studies. 26,[42][43][44][45] Similarities and parallels with psoriasis 26 have been observed in lesional and perilesional hidradenitis suppurativa tissue, 26,46 with lesional nodules demonstrating mixed inflammatory infiltrates comprising T cells, dendritic cells, plasma cells, neutrophils, [47][48][49][50] and monocytes. 51 Chronic long-…”

“…90 These components of the EGFR pathway (active in the follicular infundibulum 23 ) are associated with SOX9 and Wnt signaling linked with hair cycle progression, IL-17A production 23,91 (through shared downstream Act1 activity), and epithelial cell fate, 91 all mechanisms identified in transcriptomic analysis of hidradenitis suppurativa tissues. 44,77 GSC knockdown results in IL-36a production, 92 alterations in EGFR signaling, 93 and increased sensitivity to interferon-mediated proinflammatory pathways 92 (Fig 2). POFUT-1 (identified in cases of Dowling-Degos disease associated with hidradenitis suppurativa 94,95 ) is a fucosyltransferase that is active on multiple substrates, including Notch and EGFR, 96 and is important for posttranslational modification of receptors.…”

Hidradenitis suppurativa: Infektion, Autoimmunkrankheit oder beides?

“…Genetische Prädisposition, endokrinologische Störungen, dysregulierte erworbene Immunität, bakterielle Superinfektion, Rauchen und Adipositas gehören zu den begünstigenden Faktoren [1]. Eine begrenzte Anzahl von Studien hat sich auf die Analyse molekularer Profiländerungen auf Gen-und/oder Proteinebene konzentriert [3,4] Während in akuten Läsionen eher neutrophile Abszesse zusammen mit Makrophagen, Monozyten und dendritischen Zellen zu finden sind, trifft man in chronischen Läsionen eher B-Lymphozyten und Plasmazellen. Eine antibiotische Behandlung mit Tetrazyklinen, Clindamycin, Rifampicin, Moxifloxacin, Metronidazol und Ertapenem hat sich über die Jahre als gut wirksam erwiesen.…”

Hidradenitis suppurativa: Infektion, Autoimmunkrankheit oder beides?

“…Genetische Prädisposition, endokrinologische Störungen, dysregulierte erworbene Immunität, bakterielle Superinfektion, Rauchen und Adipositas gehören zu den begünstigenden Faktoren [1]. Eine begrenzte Anzahl von Studien hat sich auf die Analyse molekularer Profiländerungen auf Gen-und/oder Proteinebene konzentriert [3,4]. Die betroffenen Signalwege sind hauptsächlich mit Inflammation assoziiert, einschließlich Zelladhäsion, Diapedese und Extravasation sowie Signal-und Kommunikationswegen für Immunzellen [3].…”

“…Eine begrenzte Anzahl von Studien hat sich auf die Analyse molekularer Profiländerungen auf Gen-und/oder Proteinebene konzentriert [3,4]. Die betroffenen Signalwege sind hauptsächlich mit Inflammation assoziiert, einschließlich Zelladhäsion, Diapedese und Extravasation sowie Signal-und Kommunikationswegen für Immunzellen [3]. Im Artikel von Constantinou, Fragoulis und Nikiphorou wird die aktuelle Evidenz zu Verbindungen zwischen HS und Autoimmun-und Infektionskrankheiten mit einem Schwerpunkt auf Epidemiologie und Pathophysiologie untersucht.…”