Background Hidradenitis suppurativa (HS) is a chronic, inflammatory disease of the apocrine gland-rich (AGR) skin region. The initial steps of disease development are not fully understood, despite intense investigations into immune alterations in lesional HS skin.Objectives We aimed to systematically investigate the inflammatory molecules involved in three stages of HS pathogenesis, including healthy AGR, non-lesional HS and lesional HS skin, with the parallel application of multiple mRNA and protein-based methods.

The chemical milieu, microbiota composition, and immune activity show prominent differences in distinct healthy skin areas. The objective of the current study was to compare the major permeability barrier components (stratum corneum and tight junction (TJ)), investigate the distribution of (corneo)desmosomes and TJs, and measure barrier function in healthy sebaceous gland-rich (SGR), apocrine gland-rich (AGR), and gland-poor (GP) skin regions. Molecules involved in cornified envelope (CE) formation, desquamation, and (corneo)desmosome and TJ organization were investigated at the mRNA and protein levels using qRT-PCR and immunohistochemistry. The distribution of junction structures was visualized using confocal microscopy. Transepidermal water loss (TEWL) functional measurements were also performed. CE intracellular structural components were similarly expressed in gland-rich (SGR and AGR) and GP areas. In contrast, significantly lower extracellular protein levels of (corneo)desmosomes (DSG1 and CDSN) and TJs (OCLN and CLDN1) were detected in SGR/AGR areas compared to GP areas. In parallel, kallikrein proteases were significantly higher in gland-rich regions. Moreover, gland-rich areas were characterized by prominently disorganized junction structures ((corneo)desmosomes and TJs) and significantly higher TEWL levels compared to GP skin, which exhibited a regular distribution of junction structures. According to our findings, the permeability barrier of our skin is not uniform. Gland-rich areas are characterized by weaker permeability barrier features compared with GP regions. These findings have important clinical relevance and may explain the preferred localization of acantholytic skin diseases on gland-rich skin regions (e.g., Pemphigus foliaceus, Darier’s disease, and Hailey–Hailey disease).

Hidradenitis suppurativa (HS) is a Th1/17-driven inflammatory skin disease of the apocrine gland-rich (AGR) skin regions, where keratinocytes seem to be the crucial drivers of the initial pathogenic steps. However, the possible role of permeability barrier alteration in activating keratinocytes during HS development has not been clarified. We compared the major permeability barrier elements of non-lesional HS (HS-NL; n = 10) and lesional HS (HS-L; n = 10) skin with healthy AGR regions (n = 10) via RT-qPCR and immunohistochemistry. Stratum corneum components related to cornified envelope formation, corneocyte desquamation and (corneo)desmosome organization were analyzed along with tight junction molecules and barrier alarmins. The permeability barrier function was also investigated with transepidermal water loss (TEWL) measurements (n = 16). Junction structures were also visualized using confocal microscopy. At the gene level, none of the investigated molecules were significantly altered in HS-NL skin, while 11 molecules changed significantly in HS-L skin versus control. At the protein level, the investigated molecules were similarly expressed in HS-NL and AGR skin. In HS-L skin, only slight changes were detected; however, differences did not show a unidirectional alteration, as KRT1 and KLK5 were detected in decreased levels, and KLK7, KRT6 and DSG1 in increased levels. No significant differences in TEWL or the expression of junction structures were assessed. Our findings suggest that the permeability barrier is not significantly damaged in HS skin and permeability barrier alterations are not the driver factors of keratinocyte activation in this disease.

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Adiponectin enhances human keratinocyte lipid synthesis via SIRT1 and nuclear hormone receptor signaling. In an effort to put adiponectin signaling into practical use for the improvement of skin barrier function, the effects of a newly synthesized adiponectin-derived peptide (Adi-pep D) on keratinocyte lipid synthesis and differentiation were evaluated in vitro and in vivo. Adi-pep D induced adiponectin receptor activity by receptor-mediated endocytosis in HaCaT cells Further, in Adi-pep D-treated primary human keratinocytes, Adi-pep D increased the expression of the lipid synthesis enzymes HMG CoA reductase and serinepalmitoyl transferase mRNA as well as the lipid transporter ABCA12, which is related to the homeostasis of skin barrier function. The expression levels of the transcription factors SIRT1, LXRa, and SREBP also increased. Nile red fluorescence staining showed an increase in the neutral lipid content in Adi-pep-treated keratinocytes. Adi-pep D also increased the expression of epidermal differentiation marker proteins (e.g., filaggrin, involucrin, and loricrin) in HaCaT cells. We further evaluated whether the synthetic peptide can reduce the deterioration of barrier function by the topical application of a highly potent corticosteroid on murine skin. Functionally, the basal transepidermal waterloss and stratum corneum hydration levels were not different but the barrier recovery rate and integrity tended to be better than those of the non-treated skin. When the epidermis was observed by transmission electron microscopy, the count and secretion of the lamellar body in the stratum corneum-granulosa interface were significantly increased. These results suggest that the newly synthesized Adi-pep can improve lipid synthesis, differentiation, and the recovery of skin barrier function.

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