Journal Article

Glycogen metabolism regulates macrophage-mediated acute inflammatory responses

Tang, Ke, Wei, Keke, Liu, Jincheng, Ma, Jingwei, Zhang, Huafeng, Zeng, Liping, Xu, Pingwei, Chen, Jie, Tang, Liang, Sun, Weiwei, Wang, Dianheng, Xie, Jing, Huang, Bo, Liu, Junwei, Zhu, Liyan, Fang, Haiqing, Li, Fei, Liu, Yuying

2020

Overview

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-γ/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 RARβ 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/109 / 13/89 / 14 / 14/19 / 14/28 / 38 / 38/77 / 59 / 631/250/2504/342 / 631/80/221 / 692/699/255 / 96 / 96/1 / Animal models / Animals / Blotting, Western / Cell activation / Cells, Cultured / Enzyme-Linked Immunosorbent Assay / Female / Gene Silencing - physiology / Glutathione / Glycogen / Glycogen - metabolism / Glycogens / Humanities and Social Sciences / Humans / Inflammation - metabolism / Inflammatory diseases / Interleukin-4 - metabolism / Leukocytes, Mononuclear - metabolism / Lipopolysaccharides / Macrophages / Macrophages - metabolism / Metabolic pathways / Metabolism / Mice / Mice, Inbred C57BL / multidisciplinary / NADP / Pentose / Pentose phosphate pathway / Phosphorylation / Reactive Oxygen Species - metabolism / Real-Time Polymerase Chain Reaction / Receptors / Science / Science (multidisciplinary) / Sepsis / Signal Transduction / Stat1 protein / THP-1 Cells / γ-Interferon