ammation by altering histones and transcription factors such as NFB and AP1. Mounting evidence supports that inflammation sequentially links immune, metabolic, and MGCD516 chemical information mitochondrial bioenergy networks; sirtuins are essential regulators of these networks. This review focuses on how sirtuins contribute to dynamic shifts in immunity, metabolism, and bioenergy during inflammation and selective chronic and acute inflammatory PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19837474 diseases and may provide novel therapeutic targets. Several general concepts are relevant to the role of sirtuins in inflammation: The requirement for NAD+ as cofactor supports sirtuin function 
in redox and bioenergy sensing. While sirtuin-dependent deacetylation activities dominateour present understanding of the functional roles of sirtuins in inflammation, other attributes such as ADP ribosylation and removal of succinyl, malonyl, and glutamyl groups from lysine residues may be important in inflammation. Acetyl CoA levels and its support of histone-acetylation and other proteins are linked to nutritional status of cell. Fasted or survival state of cell utilizes protein deacetylation with SIRT. SIRT effects on inflammation can be a double edged sword, since low levels accentuate early acute inflammation-related autotoxicity by increasing NFB RelA/p65 activity, and prolonged increases in SIRT1 during late inflammation are associated with immunosuppression and increased mortality. Journal of Immunology Research surge and decrease in mitochondrial glucose oxidation are dependent upon HIF-1. HIF-1 in turn is regulated by PKM2 and NF kappa B. Thus, HIF1- provides a bridge between glucose metabolism and inflammation. Sirtuins, especially SIRT6, are known to be a master regulator of glycolysis. Evidence suggests that SIRT6 is a corepressor of glycolysis. Thus, glucose use for glycolysis generates effector responses needed for microbial defense including ROS generation from NOX proteins and release of antimicrobial proteins such as porins, anabolic pathways coupled to nucleus acid, fatty acid, and protein synthetic pathways, and aerobic and anaerobic glycolysis which also supply rapidly needed ATP from high glucose flux as well as very early pyruvate oxidation to feed electron transport chain. Later this fuel is shifted to fatty acids because of closure of the pyruvate portal. The switch away from high levels of reducing agents to NAD+ dominance supports the cellular “mending” pathway, which is a low ATP generating catabolic state. The anti-inflammatory response of macrophages requires fatty acid oxidation. We now know that a metabolism shifts from glycolysis to fatty acid oxidation in macrophages after LPS stimulation. This increase in fatty acid oxidation occurs via expression of PGC-1 and PGC-1. SIRT1 and SIRT6 regulate the metabolic switch in monocytes from glycolysis to fatty acid oxidation during adaptation to acute inflammation. This catabolic state supports repressor not only M2 like monocytes and macrophages, but also T repressor cells. The immunosuppression that accompanies severe systemic inflammation is generated by an inflexible persistence of the repressor homeostasis axis, which limits a secondary response to new stress–for example, like bacterial and viral original or secondary opportunistic infections. 2. Inflammation and Metabolism Evidence suggests that the sequential course of inflammation is linked with metabolism. Several recent studies have connected inflammation with glycolysis and fatty acids to provide n
