Redox regulation in metabolic programming and inflammation.
Redox regulation in metabolic programming and inflammation.
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DOI：
10.1016/j.redox.2017.01.023
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发表时间：
2017-08
期刊：
影响因子：
11.4
通讯作者：
Pararasa C
中科院分区：
文献类型：
--
作者：
Griffiths HR;Gao D;Pararasa C
能量代谢与氧化还原状态有着内在的联系。为了产生足够的免疫应答，细胞必须具有足够且快速可用的能量资源以迁移到炎症部位，使用NADPH作为辅因子产生活性氧并吞噬细菌或受损组织。先天免疫反应的第一反应细胞，中性粒细胞，在很大程度上依赖于糖酵解。嗜中性粒细胞的寿命相对较短，在通过产生次氯酸和释放细胞外NET杀死细菌的过程中通过细胞凋亡而死亡。后来，最普遍募集的先天免疫细胞是单核细胞。它们的作用是完成由中性粒细胞启动的损伤限制运动，然后作为重编程的M2巨噬细胞来解决炎症事件。大约25年前，人们注意到巨噬细胞在用皮质类固醇治疗后失去其糖酵解能力并变得抗炎。为了支持这一点，我们现在了解到，与早期反应者相反，M2巨噬细胞主要依赖于氧化磷酸化来获得能量。在早期炎症期间，向M1巨噬细胞的极化依赖于NOX 2活化，NOX 2活化通过蛋白酪氨酸磷酸酶氧化和AKT活化，增加葡萄糖转运蛋白向膜的运输，从而增加糖酵解的葡萄糖摄取。与此同时，线粒体的效率可能会受到损害，通过亚硝基化的电子传递链。炎症的消退是通过与暴露氧化磷脂酰丝氨酸的凋亡膜相遇而触发的，所述氧化磷脂酰丝氨酸与清道夫受体CD36相互作用。在CD36下游，AMPK和PPARγ的活化促进M2巨噬细胞中线粒体生物合成、磷酸化酶表达和向氧化磷酸化的转变。M2细胞产生的促炎细胞因子减少，但维持抗炎和伤口愈合生长因子的产生以支持正常功能的恢复。
Energy metabolism and redox state are intrinsically linked. In order to mount an adequate immune response, cells must have an adequate and rapidly available energy resource to migrate to the inflammatory site, to generate reactive oxygen species using NADPH as a cofactor and to engulf bacteria or damaged tissue. The first responder cells of the innate immune response, neutrophils, are largely dependent on glycolysis. Neutrophils are relatively short-lived, dying via apoptosis in the process of bacterial killing through production of hypochlorous acid and release of extracellular NETs. Later on, the most prevalent recruited innate immune cells are monocytes. Their role is to complete a damage limitation exercise initiated by neutrophils and then, as re-programmed M2 macrophages, to resolve the inflammatory event. Almost twenty five years ago, it was noted that macrophages lose their glycolytic capacity and become anti-inflammatory after treatment with corticosteroids. In support of this we now understand that, in contrast to early responders, M2 macrophages are predominantly dependent on oxidative phosphorylation for energy. During early inflammation, polarisation towards M1 macrophages is dependent on NOX2 activation which, via protein tyrosine phosphatase oxidation and AKT activation, increases trafficking of glucose transporters to the membrane and consequently increases glucose uptake for glycolysis. In parallel, mitochondrial efficiency is likely to be compromised via nitrosylation of the electron transport chain. Resolution of inflammation is triggered by encounter with apoptotic membranes exposing oxidised phosphatidylserine that interact with the scavenger receptor, CD36. Downstream of CD36, activation of AMPK and PPARγ elicits mitochondrial biogenesis, arginase expression and a switch towards oxidative phosphorylation in the M2 macrophage. Proinflammatory cytokine production by M2 cells decreases, but anti-inflammatory and wound healing growth factor production is maintained to support restoration of normal function.