小柯机器人

美国哈佛医学院布莱根妇女医院Francisco J. Quintana研究组的一项最新研究，发现胞质磷脂酶A2（cPLA2）-粒体抗病毒信号蛋白（MAVS）通过代谢调控星形胶质细胞的致病性。2019年12月5日，《细胞》在线发表了这项成果。

通过蛋白质组学、代谢组学、转录组学和摄动研究相结合的方法，研究人员发现星形胶质细胞中鞘脂代谢引起胞质磷脂酶A2（cPLA2）C2结构域与线粒体抗病毒信号蛋白（MAVS）的CARD结构域相互作用，激活NF-κB驱动的转录程序，可在实验性变态反应性脑脊髓炎（EAE）以及潜在的多发性硬化症中促进中枢神经系统（CNS）炎症。

cPLA2招募到MAVS破坏了MAVS-己糖激酶2（HK2）间的相互作用，降低了HK的酶活性以及参与维持神经元代谢的乳酸的产生。Miglustat是一种用于治疗Gaucher和Niemann-Pick疾病的药物，可抑制星形胶质细胞的致病性并改善EAE。总的来说，这些发现定义了一种新的免疫代谢机制，该机制可以激活促炎性星形胶质细胞活动，并概述了MAVS在中枢神经系统炎症中的新作用，以及为治疗提供了候选靶点。

据悉，代谢可调控外周免疫，但对其在CNS炎症中的作用知之甚少。

附：英文原文

Title: Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS

Author: Chun-Cheih Chao, Cristina Gutiérrez-Vázquez, Veit Rothhammer, Lior Mayo, Michael A. Wheeler, Emily C. Tjon, Stephanie E.J. Zandee, Manon Blain, Kalil Alves de Lima, Maisa C. Takenaka, Julian Avila-Pacheco, Patrick Hewson, Lei Liu, Liliana M. Sanmarco, Davis M. Borucki, Gabriel Z. Lipof, Sunia A. Trauger, Clary B. Clish, Jack P. Antel, Alexandre Prat, Francisco J. Quintana

Issue&Volume: December 05, 2019

Abstract: Metabolism has been shown to control peripheral immunity, but little is known aboutits role in central nervous system (CNS) inflammation. Through a combination of proteomic,metabolomic, transcriptomic, and perturbation studies, we found that sphingolipidmetabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipaseA2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS),boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimentalautoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitmentto MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymaticactivity and the production of lactate involved in the metabolic support of neurons.Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocytepathogenic activities and ameliorates EAE. Collectively, these findings define a novelimmunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlinesa new role for MAVS in CNS inflammation, and identifies candidate targets for therapeuticintervention.

DOI: 10.1016/j.cell.2019.11.016

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31272-3