Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1.
Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1.
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DOI：
10.3389/fimmu.2021.733921
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发表时间：
2021
影响因子：
7.3
通讯作者：
Pence BD
中科院分区：
文献类型：
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作者：
Cory TJ;Emmons RS;Yarbro JR;Davis KL;Pence BD
COVID-19的一个标志是与严重程度相关的高度炎症状态。单核细胞在SARS-CoV-2刺激下发生代谢重编程并产生炎性细胞因子。我们假设病毒刺突蛋白的结合介导了这种效应，并且调节免疫代谢的药物可以抑制炎症反应。重组SARS-CoV-2刺突蛋白亚基1刺激的单核细胞显示出与促炎细胞因子产生相关的糖酵解代谢的剂量依赖性增加。这种反应依赖于缺氧诱导因子-1 α，因为chetomin抑制糖酵解和细胞因子的产生。糖酵解代谢的抑制2-脱氧葡萄糖（2-DG）或葡萄糖剥夺也抑制了糖酵解反应，2-DG强烈抑制细胞因子的产生。葡萄糖剥夺的单核细胞通过上调氧化磷酸化来挽救细胞因子的产生，由于已知2-DG对抑制线粒体代谢的作用，这种作用在2-DG处理的单核细胞中不存在。最后，用二甲双胍预处理单核细胞强烈抑制刺突蛋白介导的细胞因子产生和代谢重编程。同样，二甲双胍预处理在直接感染实验中阻断了SARS-CoV-2菌株WA 1/2020的细胞因子诱导。总之，SARS-CoV-2刺突蛋白诱导单核细胞中的促炎免疫代谢反应，该反应可被二甲双胍抑制，二甲双胍同样抑制对活SARS-CoV-2的炎症反应。这对COVID-19期间炎症过度的治疗具有潜在意义。
A hallmark of COVID-19 is a hyperinflammatory state associated with severity. Monocytes undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism associated with production of pro-inflammatory cytokines. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production and metabolic reprogramming. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.