Department of Dermatology, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China.
Institute for Metabolic and Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong 256603, P.R. China.
Mol Med Rep. 2022 Jul;26(1). doi: 10.3892/mmr.2022.12739. Epub 2022 May 18.
IL‑17A, the effector cytokine of T helper (Th) 17 cells, plays a crucial role in the pathogenesis of psoriasis. The Notch1 and PI3K/AKT signaling pathways are implicated in Th17 cell differentiation and IL‑17A production. The present study aimed to evaluate the regulatory effect of the Notch1/hairy and enhancer of split 1 (Hes1)‑PTEN/AKT/IL‑17A feedback loop on Th17 cell differentiation via the PI3K/AKT inhibitor LY294002 in a mouse model of psoriasis. Mice were randomly divided into 3 groups: a control group, a model group [5% imiquimod (IMQ)‑induced group] and an intervention group (5% IMQ‑induced plus LY294002‑treated group). Skin structural characteristics were recorded and evaluated by hematoxylin and eosin staining. The weights of the spleens and inguinal lymph nodes were measured. Th17 cell percentage, as well as the mRNA and protein expression levels of Notch1, Notch1 intracellular domain (NICD1), Hes1, PTEN, AKT, phosphorylated (p)‑AKT, mTOR complex 1 (mTORC1), p‑mTORC1, S6 kinase (S6K)1, S6K2 and IL‑17A were detected in skin samples of the three experimental groups. Additionally, splenic mononuclear cells from model mice were treated by 10 and 50 µM LY294002 to further evaluate its regulatory effect on Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop. Increased Th17 cell percentage, increased expression of Notch1, NICD1, Hes1, AKT, p‑AKT, mTORC1, p‑mTORC1, S6K1, S6K2 and IL‑17A, and decreased PTEN levels were observed in model mice alongside marked psoriasis‑like skin inflammation, splenomegaly and lymphadenopathy. LY294002 treatment significantly alleviated the severity of psoriasis‑like skin inflammation in the intervention mice, attenuated the degree of epidermal hyperplasia and dermal inflammatory cell infiltration, and mitigated splenomegaly and lymphadenopathy. In addition, LY294002 treatment reversed the increased Th17 cell percentage, as well as the increased expression of Notch1, NICD1, Hes1, AKT, p‑AKT, mTORC1, p‑mTORC1, S6K1, S6K2 and IL‑17A, and the decreased expression of PTEN. study from 5% IMQ‑induced mouse splenic mononuclear cells presented that high dose of LY294002 exerted more obviously regulatory effect on Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop. The current findings suggested that the Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop regulates Th17 cell differentiation within the disease environment of psoriasis. Blocking the Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop may thus be a potential therapeutic method for management of psoriatic inflammation.
IL-17A 是辅助性 T 细胞（Th）17 细胞的效应细胞因子，在银屑病的发病机制中发挥着关键作用。 Notch1 和 PI3K/AKT 信号通路参与 Th17 细胞分化和 IL-17A 的产生。本研究旨在评估 Notch1/hairy 和增强子的分裂 1（Hes1）-PTEN/AKT/IL-17A 反馈回路通过 PI3K/AKT 抑制剂 LY294002 对银屑病小鼠模型中 Th17 细胞分化的调节作用。小鼠随机分为 3 组：对照组、模型组（5%咪喹莫特（IMQ）诱导组）和干预组（5%IMQ 诱导加 LY294002 治疗组）。通过苏木精和伊红染色记录和评估皮肤结构特征。测量脾和腹股沟淋巴结的重量。检测三组实验鼠皮肤组织中 Th17 细胞的百分率，以及 Notch1、Notch1 胞内结构域（NICD1）、Hes1、PTEN、AKT、磷酸化（p）-AKT、mTOR 复合物 1（mTORC1）、p-mTORC1、S6 激酶（S6K）1、S6K2 和 IL-17A 的 mRNA 和蛋白表达水平。此外，用 10 和 50 μM LY294002 处理模型鼠的脾单核细胞，进一步评估其对 Notch1/Hes1-PTEN/AKT/IL-17A 反馈回路的调节作用。模型鼠出现 Th17 细胞百分率升高、Notch1、NICD1、Hes1、AKT、p-AKT、mTORC1、p-mTORC1、S6K1、S6K2 和 IL-17A 表达增加，PTEN 水平降低，同时伴有明显的银屑病样皮肤炎症、脾肿大和淋巴结病。LY294002 治疗显著减轻了干预鼠中银屑病样皮肤炎症的严重程度，减轻了表皮过度增生和真皮炎症细胞浸润的程度，并减轻了脾肿大和淋巴结病。此外，LY294002 治疗逆转了 Th17 细胞百分率的增加，以及 Notch1、NICD1、Hes1、AKT、p-AKT、mTORC1、p-mTORC1、S6K1、S6K2 和 IL-17A 的表达增加，以及 PTEN 的表达降低。来自 5%IMQ 诱导的小鼠脾单核细胞的研究表明，高剂量的 LY294002 对 Notch1/Hes1-PTEN/AKT/IL-17A 反馈回路的调节作用更为明显。本研究结果表明，Notch1/Hes1-PTEN/AKT/IL-17A 反馈回路在银屑病的疾病环境中调节 Th17 细胞分化。阻断 Notch1/Hes1-PTEN/AKT/IL-17A 反馈回路可能是治疗银屑病炎症的一种潜在治疗方法。
