Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming
Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming
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同型半胱氨酸通过调节 PKM2 依赖性代谢重编程激活 B 细胞
DOI：
10.4049/jimmunol.1600613
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发表时间：
2017-01-01
影响因子：
4.4
通讯作者：
Wang, Xian
中科院分区：
文献类型：
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作者：
Deng, Jiacheng;Lu, Silin;Wang, Xian
免疫细胞过度激活在高同型半胱氨酸血症(HHcy)加速动脉粥样硬化的发病机制中起重要作用。同型半胱氨酸(Hcy)能刺激B细胞增殖和抗体分泌，但其作用机制仍不清楚。代谢重编程对淋巴细胞活化和效应器功能至关重要。在这项研究中，我们发现同型半胱氨酸激活的B细胞表现出氧化磷酸化和糖酵解的增加，并有向后者转移的趋势，以及戊糖磷酸途径中中间产物的积累，为细胞的生长和功能提供能量和生物合成底物。同型半胱氨酸在体内和体外均可促进B细胞丙酮酸激酶同工酶2(PKM2)的蛋白表达和糖酵解酶活性，而PKM2抑制剂紫草素可恢复Hcy诱导的B细胞的代谢变化以及B细胞的增殖和抗体分泌，表明PKM2在Hcy激活的B细胞代谢重编程中起关键作用。进一步的研究表明，雷帕霉素信号通路的Akt机制靶点参与了这一过程，雷帕霉素抑制剂雷帕霉素作为机制靶点抑制了Hcy诱导的PKM2酶活性变化和B细胞活化。值得注意的是，紫草素治疗有效地减轻了同型半胱氨酸加速的载脂蛋白E缺陷小鼠动脉粥样硬化病变的形成。总之，我们的结果表明，PKM2是支持Hcy诱导的B细胞活化和功能的代谢重编程所必需的，它可能在HHcy加速启动动脉粥样硬化的过程中发挥关键调节作用。
The overactivation of immune cells plays an important role in the pathogenesis of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis. Homocysteine (Hcy) activates B cell proliferation and Ab secretion; however, the underlying mechanisms for these effects remain largely unknown. Metabolic reprogramming is critical for lymphocyte activation and effector function. In this study, we showed that Hcy-activated B cells displayed an increase in both oxidative phosphorylation and glycolysis, with a tendency to shift toward the latter, as well as an accumulation of intermediates in the pentose phosphate pathway, to provide energy and biosynthetic substrates for cell growth and function. Mechanistically, Hcy increased both the protein expression and glycolytic enzyme activity of the pyruvate kinase muscle isozyme 2 (PKM2) in B cells, whereas the PKM2 inhibitor shikonin restored Hcy-induced metabolic changes, as well as B cell proliferation and Ab secretion both in vivo and in vitro, indicating that PKM2 plays a critical role in metabolic reprogramming in Hcy-activated B cells. Further investigation revealed that the Akt–mechanistic target of rapamycin signaling pathway was involved in this process, as the mechanistic target of rapamycin inhibitor rapamycin inhibited Hcy-induced changes in PKM2 enzyme activity and B cell activation. Notably, shikonin treatment effectively attenuated HHcy-accelerated atherosclerotic lesion formation in apolipoprotein E–deficient mice. In conclusion, our results demonstrate that PKM2 is required to support metabolic reprogramming for Hcy-induced B cell activation and function, and it might serve as a critical regulator in HHcy-accelerated initiation of atherosclerosis.