Glycogen metabolism regulates macrophage-mediated acute inflammatory responses
Glycogen metabolism regulates macrophage-mediated acute inflammatory responses
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糖原代谢调节巨噬细胞介导的急性炎症反应
DOI：
10.1038/s41467-020-15636-8
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发表时间：
2020-04-14
影响因子：
16.6
通讯作者：
Huang, Bo
中科院分区：
文献类型：
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作者：
Ma, Jingwei;Wei, Keke;Huang, Bo
我们目前对糖代谢如何影响巨噬细胞中的炎症通路的理解是不完整的。在这里，我们表明，糖原代谢是一个重要的事件，控制巨噬细胞介导的炎症反应。IFN-γ/LPS处理刺激巨噬细胞合成糖原，然后通过糖原分解引导糖原以产生G6P，并进一步通过戊糖磷酸途径产生丰富的NADPH，确保高水平的还原型谷胱甘肽用于炎性巨噬细胞存活。同时，糖原代谢还增加巨噬细胞中的UDPG水平和受体P2Y（14）。UDPG/P2Y（14）信号通路不仅通过激活RAR β上调STAT1的表达，而且通过下调磷酸酶TC 45促进STAT1磷酸化。在多种小鼠模型中，这种糖原代谢途径的阻断破坏了急性炎症反应。糖原代谢还调节脓毒症患者的炎症反应。这些发现表明，巨噬细胞中的糖原代谢是一种重要的调节剂，并表明可能用于治疗急性炎症性疾病的策略。糖原可以通过糖原分解和戊糖磷酸途径代谢，以及产生UDP葡萄糖，其在分泌时可以结合P2Y（14）受体。在这里，作者展示了这些糖原代谢途径如何促进促炎性巨噬细胞活化和对脓毒症的易感性。
Our current understanding of how sugar metabolism affects inflammatory pathways in macrophages is incomplete. Here, we show that glycogen metabolism is an important event that controls macrophage-mediated inflammatory responses. IFN-gamma /LPS treatment stimulates macrophages to synthesize glycogen, which is then channeled through glycogenolysis to generate G6P and further through the pentose phosphate pathway to yield abundant NADPH, ensuring high levels of reduced glutathione for inflammatory macrophage survival. Meanwhile, glycogen metabolism also increases UDPG levels and the receptor P2Y(14) in macrophages. The UDPG/P2Y(14) signaling pathway not only upregulates the expression of STAT1 via activating RAR beta but also promotes STAT1 phosphorylation by downregulating phosphatase TC45. Blockade of this glycogen metabolic pathway disrupts acute inflammatory responses in multiple mouse models. Glycogen metabolism also regulates inflammatory responses in patients with sepsis. These findings show that glycogen metabolism in macrophages is an important regulator and indicate strategies that might be used to treat acute inflammatory diseases. Glycogen can be metabolized via glycogenolysis and the pentose phosphate pathway as well as into the production of UDP glucose, which when secreted can bind the P2Y(14) receptor. Here the authors show how these glycogen metabolism pathways contribute to proinflammatory macrophage activation and susceptibility to sepsis.