Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS
Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS
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DOI：
10.1016/j.cell.2019.11.016
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发表时间：
2019-12-12
期刊：
影响因子：
64.5
通讯作者：
Quintana, Francisco J.
中科院分区：
文献类型：
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作者：
Chao, Chun-Cheih;Gutierrez-Vazquez, Cristina;Quintana, Francisco J.
代谢已被证明可以控制外周免疫，但对其在中枢神经系统（CNS）炎症中的作用知之甚少。通过蛋白质组学、代谢组学、转录组学和扰动研究的结合，我们发现星形胶质细胞中的鞘脂代谢触发了胞浆磷脂酶A2（cPLA 2）中的C2结构域与线粒体抗病毒信号蛋白（MAVS）中的CARD结构域的相互作用，促进了NF-κ B驱动的转录程序，这些转录程序促进了实验性自身免疫性脑脊髓炎（EAE）中的CNS炎症，并且可能，多发性硬化cPLA 2向MAVS的募集也破坏MAVS-己糖激酶2（HK 2）相互作用，降低HK酶活性和参与神经元代谢支持的乳酸的产生。Miglu-stat是一种用于治疗戈谢病和尼曼-匹克病的药物，可抑制星形胶质细胞致病活性并改善EAE。总的来说，这些研究结果定义了一种新的免疫代谢机制，驱动促炎星形胶质细胞的活动，概述了MAVS在CNS炎症中的新作用，并确定了治疗干预的候选靶点。
Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS), boosting NF-kappa B-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglu-stat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention.