Leptin modulates the differentiation of keratinocytes via autophagy in patients with psoriasis and metabolic syndrome

Abstract

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: We measured the epidermal leptin, P62, and LC3 concentrations by immunohistochemistry, and measured the serum leptin concentrations by enzyme-linked immunosorbent assay. We then performed correlation analyses to compare these concentrations between 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. Next, we transfected ATG5 to revert autophagy and used the specific PI3K inhibitor LY294002 to block PI3K/AKT/mTOR signaling. The expression levels of K10, K16, and K17 were again measured. One-way ANOVA was used for the comparison of means of multiple samples, and Tukey's post hoc test was used for comparison between the 2 groups. The counting data were analyzed by the chi-square test. Correlations were evaluated by Pearson correlation analysis. Results: The serum and epidermal leptin concentrations were significantly higher in patients with concomitant psoriasis and MS than in healthy control individuals and patients with psoriasis without MS (serum leptin concentrations: 1330 ± 244.2, 1041 ± 282.7, and 760.4 ± 361.1 pg/mL, P <0.0001; epidermal leptin concentrations 0.589 ± 0.151, 0.393 ± 0.125, and 0.266 ± 0.191 pg/mL, P <0.0001). The level of the autophagy marker LC3 was strongly reduced and that of P62 was strongly increased in the epidermis of patients with concomitant psoriasis and MS compared with healthy control individuals and patients with psoriasis without MS (LC3: 0.274 ± 0.113, 0.291 ± 0.128, and 0.462 ± 0.169, P <0.0001; P62: 0.185 ± 0.075, 0.132 ± 0.030, and 0.099 ± 0.031, P <0.0001). We also observed a positive correlation between leptin and P62 concentrations in the blood ( r =0.4028, P =0.0002) and epidermis ( r =0.2721, P =0.0174), and a negative correlation between serum leptin concentrations and epidermal LC3 concentrations ( r =-0.3944, P =0.0004). In vitro, leptin significantly decreased the autophagy markers Beclin1 and LC3B and increased P62. Western blotting showed that leptin treatment resulted in decreased expression of the differentiation marker 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 p-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. It is very important to optimize the treatment of patients with concomitant psoriasis and MS. Our study enhances the understanding of the link between MS and psoriasis and provides potential therapeutic targets for patients with concomitant psoriasis and MS.