Cyclin-Dependent Kinase 7 Promotes Th17/Th1 Cell Differentiation in Psoriasis by Modulating Glycolytic Metabolism.

Excessive activation of CD4+ T cells and Th17/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 CDK7 expression was markedly increased in CD4+ T cells from psoriasis patients compared with healthy controls, and was positively correlated with psoriasis severity. Meanwhile, genetic or pharmacological inhibition of CDK7 ameliorated the severity of psoriasis in 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 psoriasis patients. Proinflammatory cytokine IL-23 induced increased CDK7 expression in CD4+ T cells, and activated AKT/mTOR/HIF-1α signaling pathway, enhancing glycolytic metabolism. Correspondingly, CDK7 inhibition significantly impaired IL-23-induced glycolysis via the AKT/mTOR/HIF-1α pathway. In summary, our study demonstrates that CDK7 promotes CD4+ T cell activation and Th17/Th1 cell differentiation by regulating glycolysis, thus contributes to the pathogenesis of psoriasis. Targeting CDK7 might be a promising immunosuppressive strategy to control skin inflammation mediated by IL-23.