scholarly journals Contribution of GATA6 to homeostasis of the human upper pilosebaceous unit and acne pathogenesis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Bénédicte Oulès ◽  
Christina Philippeos ◽  
Joe Segal ◽  
Matthieu Tihy ◽  
Matteo Vietri Rudan ◽  
...  
Keyword(s):  
Lipid Production ◽  
Inflammatory Skin Disease ◽  
Pilosebaceous Unit ◽  
Junctional Zone ◽  
Normal Human Skin ◽  
Keratinocyte Proliferation ◽  
Proliferation And Differentiation ◽  
Tgfβ Signalling ◽  
Normal Human ◽  
Pathological Event

Abstract Although acne is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, notably by upregulating PD-L1 and IL10. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFβ signalling. We conclude that GATA6 is involved in regulation of the upper pilosebaceous unit and may be an actionable target in the treatment of acne.

scholarly journals Regulation of epithelial–mesenchymal IL-1 signaling by PPARβ/δ is essential for skin homeostasis and wound healing

2009 ◽  
Vol 184 (6) ◽  
pp. 817-831 ◽  
Author(s):  
Han Chung Chong ◽  
Ming Jie Tan ◽  
Virginie Philippe ◽  
Siew Hwey Tan ◽  
Chek Kun Tan ◽  
...  
Keyword(s):  
Wound Healing ◽  
Interleukin 1 ◽  
Dermal Fibroblasts ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Keratinocyte Proliferation ◽  
Proliferation And Differentiation ◽  
Keratinocyte Cell ◽  
Normal Human ◽  
Skin Morphogenesis

Skin morphogenesis, maintenance, and healing after wounding require complex epithelial–mesenchymal interactions. In this study, we show that for skin homeostasis, interleukin-1 (IL-1) produced by keratinocytes activates peroxisome proliferator–activated receptor β/δ (PPARβ/δ) expression in underlying fibroblasts, which in turn inhibits the mitotic activity of keratinocytes via inhibition of the IL-1 signaling pathway. In fact, PPARβ/δ stimulates production of the secreted IL-1 receptor antagonist, which leads to an autocrine decrease in IL-1 signaling pathways and consequently decreases production of secreted mitogenic factors by the fibroblasts. This fibroblast PPARβ/δ regulation of the IL-1 signaling is required for proper wound healing and can regulate tumor as well as normal human keratinocyte cell proliferation. Together, these findings provide evidence for a novel homeostatic control of keratinocyte proliferation and differentiation mediated via PPARβ/δ regulation in dermal fibroblasts of IL-1 signaling. Given the ubiquitous expression of PPARβ/δ, other epithelial–mesenchymal interactions may also be regulated in a similar manner.

scholarly journals The psoriatic shift induced by interleukin 17 is promptly reverted by a specific anti-IL-17A agent in a three-dimensional organotypic model of normal human skin culture

2020 ◽  
Vol 64 (2) ◽  
Author(s):  
Elena Donetti ◽  
Giulia Lombardo ◽  
Serena Indino ◽  
Laura Cornaghi ◽  
Francesca Arnaboldi ◽  
...  
Keyword(s):  
Human Skin ◽  
Three Dimensional ◽  
Aesthetic Surgery ◽  
Clinical Effectiveness ◽  
Control Group ◽  
Interleukin 17 ◽  
Normal Human Skin ◽  
Transmission Electron Microscopy Analysis ◽  
Keratinocyte Proliferation ◽  
Normal Human

Interleukin 17A (IL-17A), mainly produced by the T helper subclass Th17, plays a key role in the psoriatic plaque formation and progression. The clinical effectiveness of anti-IL-17A agents is documented, but the early and specific mechanisms of their protection are not identified yet. The challenge of the present study is to investigate the possible reversal exerted by a specific anti-IL-17A agent on the psoriatic events induced by IL-17A in a three-dimensional organotypic model of normal human skin. Bioptic skin fragments obtained after aesthetic surgery of healthy women (n=5) were incubated with i) IL-17A biological inhibitor (anti-IL-17A), ii) IL-17A, iii) a combination of IL-17A and its specific IL-17A biological inhibitor (COMBO). A Control group was in parallel cultured and incubation lasted for 24 and 48 h epidermal-side-up at the air-liquid interface. All subjects were represented in all experimental groups at all considered time-points. Keratinocyte proliferation and the presence of epidermal Langerhans cells were quantitatively estimated. In parallel with transmission electron microscopy analysis, immunofluorescence studies for the epidermal distribution of keratin (K)10, K14, K16, K17, filaggrin/occludin, Toll-like Receptor 4, and Nuclear Factor kB were performed. IL-17A inhibited cell proliferation and induced K17 expression, while samples incubated with the anti-IL-17A agent were comparable to controls. In the COMBO group the IL-17A-induced effects were almost completely reverted. Our study, for the first time, elucidates the most specific psoriatic cellular events that can be partially affected or completely reverted by a specific anti-IL-17A agent during the early phases of the plaque onset and progression. On the whole, this work contributes to expand the knowledge of the psoriatic tableau.

The use of 1nm silver enhanced gold probes for the detection of skin antigens

1990 ◽  
Vol 48 (3) ◽  
pp. 902-903
Author(s):  
J.P Cassella ◽  
H. Shimizu ◽  
A. Ishida-Yamamoto ◽  
R.A.J. Eady
Keyword(s):  
Type Iv Collagen ◽  
Freeze Substitution ◽  
Collagen Type Iv ◽  
Electron Microscopic ◽  
Normal Human Skin ◽  
Type Iv ◽  
Type Vii Collagen ◽  
Keratin Filaments ◽  
Normal Human ◽  
Phosphate Buffered Saline

1nm colloidal gold with silver enhancement has been used in conjunction with a low-temperature post-embedding (post-E) technique for the demonstration of skin antigens at both the light microscopic (LM) and electron microscopic (EM) levels.Keratin filaments and basement membrane zone (BMZ) associated antigens in normal human skin (NHS) were immunolabelled using antibodies against keratin 14, 10, and 1, the carboxy-terminus and collagenous portion of type VII collagen, type IV collagen and bullous pemphigoid antigen (BP-Ag).Fresh samples of NHS were cryoprotected in 15% glycerol, cryofixed in propane at -190°C, subjected to freeze substitution in methanol at -80°C and embedded in Lowicryl K11M at -60°C. Polymerisation of the resin was initiated under UVR at - 60°C for 48 hours and continued at room temperature for a further 48 hours. Semith in sections were air dried onto slides coated with 3-aminopropyltriethoxysilane. The following immunolabelling protocol was adopted: Primary antibody was applied for 2 hours at 37°C or overnight at 4°C. Following washing in Dulbecco’s phosphate buffered saline (PBSA) a biotinylated secondary antibody was applied for 2 hours at 37°C. The sections were further washed in PBSA and 1nm gold avidin was applied. Sections were finally washed in PBSA and silver enhanced.

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