Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Room 4A62, Bethesda, MD, 20892, USA.
Graduate School of Information Science and Technology, Hokkaido University, Sapporo, Japan.
J Mol Med (Berl). 2019 Sep;97(9):1231-1243. doi: 10.1007/s00109-019-01786-w. Epub 2019 May 3.
During infection, hepatocytes must undergo a reprioritization of metabolism, termed metabolic reprogramming. Hepatic metabolic reprogramming in response to infection begins within hours of infection, suggesting a mechanism closely linked to pathogen recognition. Following injection with polyinosinic:polycytidylic acid, a mimic of viral infection, a robust hepatic innate immune response could be seen involving the TNFα pathway at 2 h. Repeated doses led to the adoption of Warburg-like metabolism in the liver as determined by in vivo metabolic imaging, expression analyses, and metabolomics. Hepatic macrophages, Kupffer cells, were able to induce Warburg-like metabolism in hepatocytes in vitro via TNFα. Eliminating macrophages in vivo or blocking TNFα in vitro or in vivo resulted in abrogation of the metabolic phenotype, establishing an immune-metabolic axis in hepatic metabolic reprogramming. Overall, we suggest that macrophages, as early sensors of pathogens, instruct hepatocytes via TNFα to undergo metabolic reprogramming to cope with challenges to homeostasis initiated by infection. This work not only addresses a key component of end-organ physiology, but also raises questions about the side effects of biologics in the treatment of inflammatory diseases. KEY MESSAGES: • Hepatocytes develop Warburg-like metabolism in vivo during viral infection. • Macrophage TNFα promotes expression of glycolytic enzymes in hepatocytes. • Blocking this immune-metabolic axis abrogates Warburg-like metabolism in the liver. • Implications for patients being treated for inflammatory diseases with biologics.
在感染过程中，肝细胞必须对代谢进行重新优先排序，这被称为代谢重编程。感染后数小时内，肝细胞对感染的代谢重编程就开始了，这表明其与病原体识别密切相关。在注射聚肌苷酸：聚胞苷酸（一种模拟病毒感染的物质）后 2 小时，就可以观察到涉及 TNFα 途径的强大的肝脏先天免疫反应。重复给药导致肝脏采用类似于瓦伯格的代谢，这可以通过体内代谢成像、表达分析和代谢组学来确定。肝巨噬细胞（Kupffer 细胞）能够通过 TNFα 在体外诱导肝细胞产生类似于瓦伯格的代谢。在体内消除巨噬细胞或在体外或体内阻断 TNFα 会导致代谢表型被消除，从而在肝脏代谢重编程中建立了一个免疫代谢轴。总的来说，我们认为巨噬细胞作为病原体的早期传感器，通过 TNFα 指令肝细胞进行代谢重编程，以应对感染引发的内稳态挑战。这项工作不仅解决了终末器官生理学的一个关键组成部分，还提出了关于生物制剂治疗炎症性疾病的副作用的问题。
在病毒感染过程中，肝细胞在体内形成类似于瓦伯格的代谢。
巨噬细胞 TNFα 促进肝细胞中糖酵解酶的表达。
阻断这个免疫代谢轴会消除肝脏中的类似于瓦伯格的代谢。
对接受生物制剂治疗炎症性疾病的患者的影响。
