Interleukin‐17A suppresses granular layer formation in a 3‐D human epidermis model through regulation of terminal differentiation genes

Abstract

Immunotherapies targeting interleukin (IL)‐17 greatly improve plaque psoriasis. Most previous studies on IL‐17 focused on the T‐helper (Th)17 immune response, but investigation of the effects of IL‐17A on psoriatic epidermal structure are limited. Using an in vitro 3‐D human epidermis model, we investigated the effects of IL‐17A and IL‐17C on morphological changes and gene expression. IL‐17A directly suppressed the formation of the granular layer, whereas IL‐17C did not. IL‐17A significantly downregulated the gene expression of profilaggrin (FLG), which is a major component of keratohyalin granules in the granular layer. Global gene expression analysis of this 3‐D epidermis model showed that both IL‐17A and IL‐17C upregulated S100A7A and type 1 interferon‐related genes including MX1, IFI44L, XAF1 and IFIT1. However, only IL‐17A directly downregulated keratinocyte differentiation‐related and cornified envelope‐related genes including FLG, LOR, C1ORF68, LCE1E, LCE1B, KRT10, CST6 and RPTN. In conclusion, IL‐17A, a systemic inflammatory cytokine, affected keratinization in our 3‐D epidermis model. In contrast, IL‐17C, a locally produced cytokine, did not have strong effects on keratinization. Targeting IL‐17A does not only reduce inflammation but it may also directly affect epidermal differentiation in psoriasis.

Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

“…The observed improvement in the patients’ skin lesions supports the clinical importance of our findings. RNA-Seq data sets from a patient before and after treatment revealed that in addition to suppressing the inflammatory response, ustekinumab restored expression of structural/adhesive proteins important for maintaining epidermal architecture, consistent with previous reports that IL-17A can downregulate differentiation and cornified envelope-related genes ( 49 ). These adhesive proteins included the genetic target, Dsg1, which was restored at cell-cell borders in treated patient epidermis.…”

Molecular networks in atopic mothers impact the risk of infant atopy

“…Some of the strongest candidates seen in the paired mother–child transcriptomic analyses were MX1 , IFI6 , and IFIT3 , all members of the interferon signaling pathway, identified here as the most differentially expressed canonical pathway specific to maternal atopy. The shared DEGs have previously been connected to AD, 70,84,85 asthma, 86–88 and inflammatory processes 89–91 . For all nine DEGs found in mother and child pairs, eQTM relationships depending on maternal atopy were shown.…”

“…The shared DEGs have previously been connected to AD, 70,84,85 asthma, [86][87][88] and inflammatory processes. [89][90][91] For all nine DEGs found in mother and child pairs, eQTM relationships depending on maternal Determining risk factors at an epigenetic and transcriptomic level exposes many limitations given the complexity of the diseases, heterogeneity within cohorts, and sizes of the cohorts. The overall study population on a genome-wide level may be considered small.…”

Effects of IL-17 on Epidermal Development

“…The inflammation that is induced by IL-17A contributes greatly to the defense against bacterial, fungal, and viral infections, but excessive inflammation can lead to autoimmune diseases and the creation of unfortunate conditions in the skin, such as psoriasis and hidradenitis suppurativa (HS), as described below. Additionally, IL-17A is directly involved in epidermal differentiation, as described below, and this may also be related to the formation of a pathological epidermis, such as psoriasis [22][23][24].…”