A critical role for citrate metabolism in LPS signalling.
A critical role for citrate metabolism in LPS signalling.
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DOI：
10.1042/bj20111386
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发表时间：
2011-09-15
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影响因子：
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通讯作者：
O'Neill, Luke A J
中科院分区：
文献类型：
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作者：
O'Neill, Luke A J
巨噬细胞活化是炎症过程中的关键事件，因为这些细胞产生一系列促炎分子，包括ROS(活性氧种)、前列腺素、细胞因子和一氧化氮。这些因子通过引起血管扩张和中性粒细胞、单核细胞和淋巴细胞的募集来促进炎症，最终清除感染并修复受损组织。最有效的巨噬细胞激活剂之一是革兰氏阴性细菌细胞壁成分内毒素(脂多糖)。LPs被TLR4(Toll-like Receptor 4)感知，并触发高度复杂的信号通路，最终激活转录因子，如核因子kappaB，进而增加编码蛋白质的基因的转录，如COX2(前列腺素生物合成的关键酶)，一氧化氮合酶和细胞因子，如肿瘤坏死因子。最近，代谢通路在内毒素信号调节中的作用已成为炎症研究的焦点。一个值得注意的例子是内毒素促进了所谓的华宝效应--有氧糖酵解。这允许上调ATP的产生，也允许生产生物合成中间体来满足激活的巨噬细胞的需求。在这一期的《生物化学杂志》中，因凡蒂诺等人。新陈代谢在内毒素作用中的作用增加了一项新的发现。它们证明了在内毒素诱导ROS、一氧化氮和前列腺素的过程中，线粒体柠檬酸盐载体是必需的。用siRNA(小干扰RNA)击倒载体，或使用抑制剂BTA(苯-1，2，3-三羧酸盐)，就会取消这些反应。虽然没有提供机制，但作者推测乙酰辅酶A是由柠檬酸在胞浆中合成的。产生的乙酰辅酶A可能是磷脂生物合成所必需的，磷脂是生产前列腺素的花生四烯酸的来源。柠檬酸代谢的另一种产物草酰乙酸酯会间接产生一氧化氮和ROS。这一发现使从线粒体运输的柠檬酸盐成为脂多糖信号传递的关键参与者，至少在ROS、一氧化氮和前列腺素的产生方面是如此。柠檬酸盐在脂多糖作用中的这一有点出人意料的作用增加了越来越多的关于新陈代谢在炎症信号调节中的作用的文献。
Macrophage activation is a key event in the inflammatory process, since these cells produce a range of pro-inflammatory molecules, including ROS (reactive oxygen species), prostaglandins, cytokines and nitric oxide. These factors promote inflammation by causing vasodilation and recruitment of neutrophils, monocytes and lymphocytes, which ultimately clear infection and repair damaged tissue. One of the most potent macrophage activators is the Gram-negative-derived bacterial cell wall component LPS (lipopolysaccharide). LPS is sensed by TLR4 (Toll-like receptor 4) and triggers highly complex signalling pathways that culminate in activation of transcription factors such as NF-kappaB (nuclear factor kappaB), which in turn increases transcription of genes encoding proteins such as COX2 (cyclo-oxygenase 2, a key enzyme in prostaglandin biosynthesis), nitric oxide synthase and cytokines such as TNF (tumour necrosis factor). Recently, a role for metabolic pathways in the regulation of LPS signalling has become a focus of research in inflammation. A notable example is LPS promoting the so-called Warburg effect - aerobic glycolysis. This allows for an up-regulation in ATP production, and also for the production of biosynthetic intermediates to meet the demands of the activated macrophages. In this issue of the Biochemical Journal, Infantino et al. add a new finding to the role of metabolism in LPS action. They demonstrate a requirement for the mitochondrial citrate carrier in the induction of ROS, nitric oxide and prostaglandins by LPS. The knockdown of the carrier with siRNA (small interfering RNA), or the use of an inhibitor BTA (benzene-1,2,3-tricarboxylate), abolishes these responses. Although no mechanism is provided, the authors speculate that acetyl-CoA is synthesized from citrate in the cytosol. The acetyl-CoA generated could be required for phospholipid biosynthesis, the phospholipids being the source of arachidonic acid for prostaglandin production. Another product of citrate metabolism, oxaloacetate, will indirectly generate nitric oxide and ROS. This finding places citrate, transported from the mitochondria, as a key player in LPS signalling, at least for ROS, nitric oxide and prostaglandin production. This somewhat unexpected role for citrate in LPS action adds to a growing literature on the role for metabolism in the regulation of signalling in inflammation.