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Pathway Description
LPS and Citrate Signaling and Inflammation
Homo sapiens
Protein Pathway
Lipopolysaccharides (LPS) are essential to the structure and function of the Gram-negative bacterial outer membrane, providing both stability (via an increased negative charge) and protection. Also referred to as lipoglycans and endotoxins, these large molecules are potent activators of animal immune systems. Following detection by macrophage and dendritic cell TLR4 (Toll-like receptor 4), signalling cascades activate transcription factors such as NF-κB which lead to the production of pro-inflammatory molecules (e.g. cytokines, prostaglandins, ROS, and nitric oxide). Inflammation, the body's response to infection and injury, is vital for the elimination of harmful irritants and the initiation of tissue repair. The production of citrate is upregulated in LPS-activated dendritic cells (via upregulation of glycolysis) in order to increase the rate of fatty acid biosynthesis. Fatty acids are vital for cytokine production and for extending the cell membrane in order to allow for more antigens to be presented. A mitochondrial citrate transport protein exports citrate into the cytoplasm where it is catabolized into acetyl-CoA and oxaloacetate. Acetyl-CoA is incorporated into phospholipids and used to acetylate proteins. Oxaloacetate can be broken down further into NADPH which is required to synthesize reactive oxygen species (ROS) and nitric oxide (NO).
References
LPS and Citrate Signaling and Inflammation References
Iacobazzi V, Infantino V: Citrate--new functions for an old metabolite. Biol Chem. 2014 Apr;395(4):387-99. doi: 10.1515/hsz-2013-0271.
Pubmed: 24445237
Ashbrook MJ, McDonough KL, Pituch JJ, Christopherson PL, Cornell TT, Selewski DT, Shanley TP, Blatt NB: Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses. Clin Exp Immunol. 2015 Jun;180(3):520-30. doi: 10.1111/cei.12591. Epub 2015 Apr 19.
Pubmed: 25619261
Mills E, O'Neill LA: Succinate: a metabolic signal in inflammation. Trends Cell Biol. 2014 May;24(5):313-20. doi: 10.1016/j.tcb.2013.11.008. Epub 2013 Dec 19.
Pubmed: 24361092
Williams NC, O'Neill LAJ: A Role for the Krebs Cycle Intermediate Citrate in Metabolic Reprogramming in Innate Immunity and Inflammation. Front Immunol. 2018 Feb 5;9:141. doi: 10.3389/fimmu.2018.00141. eCollection 2018.
Pubmed: 29459863
O'Neill LA: A critical role for citrate metabolism in LPS signalling. Biochem J. 2011 Sep 15;438(3):e5-6. doi: 10.1042/BJ20111386.
Pubmed: 21867483
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