Serine Metabolism Supports Macrophage IL-1β Production
Serine Metabolism Supports Macrophage IL-1β Production
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DOI：
10.1016/j.cmet.2019.01.014
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发表时间：
2019-04-02
期刊：
影响因子：
29
通讯作者：
Chandel, Navdeep S.
中科院分区：
文献类型：
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作者：
Rodriguez, Arianne E.;Ducker, Gregory S.;Chandel, Navdeep S.
丝氨酸是核苷酸、NADPH 和谷胱甘肽 (GSH) 合成的底物。先前对癌细胞和淋巴细胞的研究表明，丝氨酸依赖性一碳单位对于核苷酸产生以支持增殖是必需的。目前，尚不清楚丝氨酸代谢是否影响非增殖细胞（例如炎症巨噬细胞）的功能。我们发现，在巨噬细胞中，丝氨酸是脂多糖 (LPS) 最佳诱导 IL-1 β mRNA 表达所必需的，但不需要丝氨酸激活炎症小体。该机制涉及需要甘氨酸（由丝氨酸制成）来支持巨噬细胞 GSH 合成。细胞可渗透的 GSH（而非一碳供体甲酸盐）可以挽救 IL-1 β mRNA 的表达。体内丝氨酸从头合成的药理抑制可降低 LPS 对 IL-1 β 水平的诱导，并提高 LPS 驱动的小鼠脓毒症模型的存活率。我们的研究表明，丝氨酸代谢是 GSH 合成所必需的，以支持 IL-1 β 细胞因子的产生。
Serine is a substrate for nucleotide, NADPH, and glutathione (GSH) synthesis. Previous studies in cancer cells and lymphocytes have shown that serine-dependent one-carbon units are necessary for nucleotide production to support proliferation. Presently, it is unknown whether serine metabolism impacts the function of non-proliferative cells, such as inflammatory macrophages. We find that in macrophages, serine is required for optimal lipopolysaccharide (LPS) induction of IL-1 beta mRNA expression, but not inflammasome activation. The mechanism involves a requirement for glycine, which is made from serine, to support macrophage GSH synthesis. Cell-permeable GSH, but not the one-carbon donor formate, rescues IL-1 beta mRNA expression. Pharmacological inhibition of de novo serine synthesis in vivo decreased LPS induction of IL-1 beta levels and improved survival in an LPS-driven model of sepsis in mice. Our study reveals that serine metabolism is necessary for GSH synthesis to support IL-1 beta cytokine production.