Cyclin-Dependent Kinase 7 Promotes Th17/Th1 Cell Differentiation in Psoriasis by Modulating Glycolytic Metabolism
Cyclin-Dependent Kinase 7 Promotes Th17/Th1 Cell Differentiation in Psoriasis by Modulating Glycolytic Metabolism
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DOI：
10.1016/j.jid.2021.04.018
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发表时间：
2021-10-20
影响因子：
6.5
通讯作者：
Li, Bing
中科院分区：
文献类型：
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作者：
Lin, Yiting;Xue, Ke;Li, Bing
CD 4（+）T细胞过度活化和辅助性T细胞（Th）17/Th 1分化是银屑病发病的关键事件，但相关的分子机制尚不清楚。在这里，我们使用定量蛋白质组学分析，发现银屑病患者的CD 4（+）T细胞中细胞周期蛋白依赖性激酶7（CDK 7）的表达与健康对照组相比显著增加，并与银屑病的严重程度呈正相关。同时，在咪喹莫特诱导的银屑病样小鼠模型中，CDK 7的遗传或药物抑制可改善银屑病的严重程度，并抑制体内和体外CD 4（+）T细胞活化以及Th 17/Th 1细胞分化。此外，CDK 7抑制剂还降低了银屑病患者CD 4（+）T细胞的糖酵解增强。促炎细胞因子IL-23诱导CD 4（+）T细胞中CDK 7表达增加，并激活蛋白激酶B/mTOR/HIF-1 α信号通路，增强糖酵解代谢。相应地，CDK 7抑制通过蛋白激酶B/mTOR/HIF-1 α途径显著损害IL-23诱导的糖酵解。总之，本研究表明CDK 7通过调节糖酵解促进CD 4（+）T细胞活化和Th 17/Th 1细胞分化，从而促进银屑病的发病。靶向CDK 7可能是控制IL-23介导的皮肤炎症的有希望的免疫抑制策略。
Excessive activation of CD4(+) T cells and T helper type (Th) 17/Th1 cell differentiation are critical events in psoriasis pathogenesis, but the associated molecular mechanism is still unclear. Here, using quantitative proteomics analysis, we found that cyclin-dependent kinase 7 (CDK7) expression was markedly increased in CD4(+) T cells from patients with psoriasis compared with healthy controls and was positively correlated with psoriasis severity. Meanwhile, genetic or pharmacological inhibition of CDK7 ameliorated the severity of psoriasis in the imiquimod-induced psoriasis-like mouse model and suppressed CD4(+) T-cell activation as well as Th17/Th1 cell differentiation in vivo and in vitro. Furthermore, the CDK7 inhibitor also reduced the enhanced glycolysis of CD4(+) T cells from patients with psoriasis. Proinflammatory cytokine IL-23 induced increased CDK7 expression in CD4(+) T cells and activated the protein kinase B/mTOR/HIF-1 alpha signaling pathway, enhancing glycolytic metabolism. Correspondingly, CDK7 inhibition significantly impaired IL-23-induced glycolysis via the protein kinase B/mTOR/HIF-1 alpha pathway. In summary, this study shows that CDK7 promotes CD4(+) T-cell activation and Th17/Th1 cell differentiation by regulating glycolysis, thus contributing to the pathogenesis of psoriasis. Targeting CDK7 might be a promising immunosuppressive strategy to control skin inflammation mediated by IL-23.