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-κB (nuclear factor κB), 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.
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August 26 2011
A critical role for citrate metabolism in LPS signalling
Luke A. J. O'Neill
Luke A. J. O'Neill
1
1School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
1email laoneill@tcd.ie
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Publisher: Portland Press Ltd
Received:
July 28 2011
Accepted:
August 02 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 438 (3): e5–e6.
Article history
Received:
July 28 2011
Accepted:
August 02 2011
Connected Content
A commentary has been published:
The mitochondrial citrate carrier: a new player in inflammation
Citation
Luke A. J. O'Neill; A critical role for citrate metabolism in LPS signalling. Biochem J 15 September 2011; 438 (3): e5–e6. doi: https://doi.org/10.1042/BJ20111386
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