Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production
Choline Uptake and Metabolism Modulate Macrophage IL-1β and IL-18 Production
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DOI：
10.1016/j.cmet.2019.03.011
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发表时间：
2019-06-04
期刊：
影响因子：
29
通讯作者：
Karin, Michael
中科院分区：
文献类型：
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作者：
Sanchez-Lopez, Elsa;Zhong, Zhenyu;Karin, Michael
胆碱是一种类似维生素的营养物质，通过特定的转运蛋白被摄取，并被胆碱激酶代谢成磷胆碱，磷脂酰胆碱(PC)是细胞膜的主要磷脂，它的从头合成所需的磷胆碱。我们发现，Toll样受体(TLR)的激活通过诱导胆碱转运体CTL1增强巨噬细胞和小胶质细胞对胆碱的摄取。抑制CTL1表达或胆碱磷酸化可减轻NLRP3炎症激活及IL-1β和IL-18的产生。从机制上讲，胆碱摄取的减少改变了线粒体的脂质分布，减弱了线粒体的ATP合成，并激活了能量传感器AMP激活的蛋白激酶(AMPK)。AMPK通过增强线粒体对Drp1的募集，刺激有丝分裂，从而有助于终止NLRP3炎性小体的激活。相应地，胆碱激酶抑制剂改善了IL-1β依赖炎症的急性和慢性模型。
Choline is a vitamin-like nutrient that is taken up via specific transporters and metabolized by choline kinase, which converts it to phosphocholine needed for de novo synthesis of phosphatidylcholine (PC), the main phospholipid of cellular membranes. We found that Toll-like receptor (TLR) activation enhances choline uptake by macrophages and microglia through induction of the choline transporter CTL1. Inhibition of CTL1 expression or choline phosphorylation attenuated NLRP3 inflammasomeactivation and IL-1 beta and IL-18 production in stimulated macrophages. Mechanistically, reduced choline uptake altered mitochondrial lipid profile, attenuated mitochondrial ATP synthesis, and activated the energy sensor AMP-activated protein kinase (AMPK). By potentiating mitochondrial recruitment of DRP1, AMPK stimulates mitophagy, which contributes to termination of NLRP3 inflammasome activation. Correspondingly, choline kinase inhibitors ameliorated acute and chronic models of IL-1 beta-dependent inflammation.