Leptin Modulates the Differentiation of Keratinocytes via Autophagy in Psoriasis Patients With Metabolic Syndrome

Objective:Psoriasis is associated with a high prevalence of metabolic syndrome(MS),and patients with concomitant psoriasis and MS are more severely affected and less responsive to treatment.However,the molecular mechanisms behind these effects are unknown.Recent studies have shown that leptin may serve as a molecular link between psoriasis and MS,suggesting that high leptin concentrations may exacerbate psoriasis.However,the molecular mechanism of this effect is still unclear.We aimed to investigate the effect of leptin on autophagy in patients with psoriasis.Methods:From January 2021 to June 2022 in PLA General Hospital,we enrolled 51 patients with psoriasis,including 21 patients with MS and 30 without MS,and 30 healthy controls who had undergone nevus surgery.We measured the epidermal leptin,P62,and LC3B concentrations of patients by immunohistochemistry,and measured the serum leptin concentration by enzyme-linked immunosorbent assay.We then performed correlation analyses to compare these proteins’concentrations between patients with concomitant psoriasis and MS,patients with psoriasis alone,and healthy control groups.Additionally,we performed western blotting after in vitro culture of HaCaT cells with different concentrations of leptin and measured the expression levels of the autophagy markers Beclin1,LC3B,and P62;the differentiation markers K10,K16,and K17;and PI3K/AKT/mTOR signaling pathway-related proteins of HaCat cells.Next,we transfected ATG5 into HaCaT cells to revert autophagy and used the specific PI3K inhibitor LY294002 to block PI3K/AKT/mTOR signaling.The expression levels of K10,K16,and K17 of HaCat cells were again measured.One-way analysis of variance was used for the comparison of means of multiple samples,and LSD-t post hoc test was used for comparison between the 2 groups.The counting data were analyzed by the chisquare test.Correlations were evaluated by Pearson correlation analysis.Results:The serum leptin concentration was significantly higher in patients with concomitant psoriasis and MS than in patients with psoriasis alone,and healthy controls(1,330.0±244.2 pg/mL,1,041.0±282.7 pg/mL,and 760.4±361.1 pg/mL,P<0.001).Optical density of epidermal leptin concentration was significantly higher in patients with psoriasis and MS than in patients with psoriasis alone and healthy controls(0.59±0.15,0.39±0.12,and 0.27±0.19,P<0.001).The level of the autophagy marker LC3B was strongly reduced and that of P62 was strongly increased in the epidermis of patients with concomitant psoriasis and MS compared with patients with psoriasis alone and healthy controls(optical density value:LC3B:0.27±0.11,0.29±0.13,and 0.46±0.17,P<0.001;P62:0.18±0.08,0.13±0.03,and 0.10±0.03,P<0.001).We also observed a positive correlation between leptin and P62 concentrations in the blood(r=0.40,P<0.001)and epidermis(r=0.27,P=0.017),and a negative correlation between serum leptin concentrations and epidermal LC3B concentrations(r=−0.39,P<0.001).In vitro,leptin significantly decreased Beclin1 and LC3B and increased P62.Western blotting showed that leptin treatment resulted in decreased expression of K10,and increased expressions of K16 and K17;when the decrease in autophagy was restored by ATG5,this phenomenon was reversed.In addition,leptin treatment significantly upregulated the expressions of phosphorylated PI3K,AKT,and mTOR in HaCaT cells compared with the control treatment;when the expression of phosphorylated PI3K was significantly inhibited by LY294002,leptin did not reverse the decreased expression of these proteins.Conclusion:Leptin is negatively associated with autophagy in psoriasis,and leptin markedly decreased autophagy and affected keratinocyte differentiation by downregulating autophagy via the PI3K/AKT/mTOR pathway.Our study enhances the understanding of leptin as the link between MS and psoriasis and provides potential therapeutic targets for patients with concomitant psoriasis and MS.

TLR3 activation induces S100A7 to regulate keratinocyte differentiation after skin injury

Human S100A7 (psoriasin) is highly expressed in psoriasis and other inflammatory diseases; however, the function of S100A7 in wound repair remains largely unknown. Here we demonstrated that skin injury increased the expression of S100A7. Damaged cells from wounded skin induced the expression of S100A7 via the activation of Toll-like receptor 3 (TLR3) followed by the activation of p38 MAPK. S100A7, in turn, acted on keratinocytes to induce the expression of terminal differentiation marker gene loricrin through the activation of p38 MAPK and caspase-1. The differentiation of keratinocytes induced by S100A7 resulted in skin stratification, thus efficiently promoting wound closure. Taken together, our results demonstrate that the activation of TLR3 accelerates wound closure via the induction of S100A7 to induce keratinocyte differentiation. These findings also provide new insights into the development of different forms of treatment with skin wounds.

Porcine Placenta Extract Reduced Wrinkle Formation by Potentiating Epidermal Hydration

Background: Placenta extract is used as an alternative medicine especially in Asian countries as it is a rich reservoir of diverse bioactive molecules. The effects of placenta extract on skin conditions have been previously reported, however, the mechanism underlying for reduced wrinkle formation remains unclear. Objective: The primary objective of this study was to determine whether the continuous application of porcine placenta extract (PPE) alleviates wrinkle formation in humans and explore the underlying mechanism. Methods: Wrinkle formation, skin hydration, and skin elasticity were measured in 15 volunteers at weeks 0 and 6 after continuous application of a gel containing PPE. The production of type I collagen and hyaluronic acid from fibroblasts and keratinocytes, respectively, were measured using ELISA. Expression levels of ceramide synthase 3 (CERS3), filaggrin (FLG), transglutaminase 1 (TGM1), and kallikrein-7 (KLK7) were evaluated by quantitative real-time PCR. Results: The wrinkle index was significantly reduced to 72.1% after a 6-week of applying the PPE gel, along with a significant increase in skin hydration to 126.5%. Type I collagen production from fibroblasts was enhanced slightly but significantly following treatment with PPE. PPE accelerated the expression of CERS3 (1.85-fold), FLG (1.35-fold), TGM1 (1.76-fold), and KLK7 (1.62-fold). Conclusion: Treatment with PPE alleviates wrinkle formation and simultaneously enhances skin hydration, which is induced via the accelerated expression of moisturizing-related proteins. These findings suggest that PPE is effective for combating dryness-induced wrinkle formation.