Liu Yun-Zi, Xu Ming-Yuan, Dai Xiao-Yu, Yan Lang, Li Lei, Zhu Rui-Zhen, Ren Li-Jun, Zhang Ji-Qian-Zhu, Zhang Xiao-Fang, Li Jin-Feng, Tian Yi-Jun, Shi Wen-Jing, Liu Ye-Qiang, Jiang Chun-Lei, Zhu Jiang-Bo, Chen Ji-Kuai
Department of Health Toxicology, Faculty of Naval Medicine, Second Military Medical University, Shanghai, China.
Laboratory of Stress Medicine, Faculty of Psychology and Mental Health, Second Military Medical University, Shanghai, China.
Front Pharmacol. 2021 Oct 18;12:765790. doi: 10.3389/fphar.2021.765790. eCollection 2021.
Psoriasis is characterized by keratinocyte proliferation and immune cell infiltration. M2 isoform of pyruvate kinase (PKM2) was reported to have an important role in cell proliferation, which is a rate-limiting enzyme that regulates the final step of glycolysis. However, how PKM2 regulates cell metabolism and proliferation in psoriatic keratinocytes is still poorly understood. Interestingly, we found that PKM2 was highly expressed in psoriatic epidermis from patients and mouse models. PKM2 overexpression promoted keratinocyte glycolytic metabolism while knockdown inhibited keratinocyte proliferation and glycolysis. Mice lacking PKM2 specifically in keratinocytes, pharmacological inhibition of PKM2 or glycolysis inhibited keratinocyte proliferation and showed obvious remission in an imiquimod-induced psoriatic mouse model. Moreover, the inhibitor of the EGF-receptor blocked EGF-stimulated PKM2 expression and glycolysis in keratinocytes. We identify PKM2 as an upregulated gene in psoriasis. PKM2 is essential in keratinocyte over-proliferation and may represent a therapeutic target for psoriasis.
银屑病的特征是角质形成细胞增殖和免疫细胞浸润。据报道，丙酮酸激酶（PKM2）的M2亚型在细胞增殖中起重要作用，它是一种调节糖酵解最后一步的限速酶。然而，PKM2如何调节银屑病角质形成细胞的细胞代谢和增殖仍知之甚少。有趣的是，我们发现PKM2在患者和小鼠模型的银屑病表皮中高表达。PKM2过表达促进角质形成细胞糖酵解代谢，而敲低则抑制角质形成细胞增殖和糖酵解。在角质形成细胞中特异性缺失PKM2的小鼠、PKM2或糖酵解的药理学抑制均抑制角质形成细胞增殖，并在咪喹莫特诱导的银屑病小鼠模型中显示出明显的缓解。此外，表皮生长因子受体抑制剂可阻断表皮生长因子刺激的角质形成细胞中PKM2的表达和糖酵解。我们确定PKM2是银屑病中上调的基因。PKM2在角质形成细胞过度增殖中至关重要，可能是银屑病的治疗靶点。
