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Review
. 2018 Sep 13;19(9):2738.
doi: 10.3390/ijms19092738.

Sirtuins and Immuno-Metabolism of Sepsis

Xianfeng Wang  1 , Nancy L Buechler  2 , Alan G Woodruff  3 , David L Long  4 , Manal Zabalawi  5 , Barbara K Yoza  6   7 , Charles E McCall  8   9 , Vidula Vachharajani  10   11
Affiliations
Review

Sirtuins and Immuno-Metabolism of Sepsis

Xianfeng Wang et al. Int J Mol Sci. .

Abstract

Sepsis and septic shock are the leading causes of death in non-coronary intensive care units worldwide. During sepsis-associated immune dysfunction, the early/hyper-inflammatory phase transitions to a late/hypo-inflammatory phase as sepsis progresses. The majority of sepsis-related deaths occur during the hypo-inflammatory phase. There are no phase-specific therapies currently available for clinical use in sepsis. Metabolic rewiring directs the transition from hyper-inflammatory to hypo-inflammatory immune responses to protect homeostasis during sepsis inflammation, but the mechanisms underlying this immuno-metabolic network are unclear. Here, we review the roles of NAD+ sensing Sirtuin (SIRT) family members in controlling immunometabolic rewiring during the acute systemic inflammatory response associated with sepsis. We discuss individual contributions among family members SIRT 1, 2, 3, 4 and 6 in regulating the metabolic switch between carbohydrate-fueled hyper-inflammation to lipid-fueled hypo-inflammation. We further highlight the role of SIRT1 and SIRT2 as potential "druggable" targets for promoting immunometabolic homeostasis and increasing sepsis survival.

Keywords: hyper-inflammation; immunosuppression; sepsis; septic shock.

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Conflict of interest statement

The authors declare no conflict of interest pertaining to this manuscript.

Figures

Figure 1
Figure 1
Immune response to sepsis: sepsis inflammation in immune cells transitions from the hyper-inflammatory to the hypo-inflammatory phase. There is increased glycolysis in the endotoxin-responsive hyper-inflammatory phase, while the endotoxin-tolerant hypo-inflammatory phase is associated with increased fatty acid oxidation in immune cells.
Figure 2
Figure 2
Aerobic glycolysis in activated immune cells: Activated immune cells undergo aerobic glycolysis; there is inhibition of oxidative phosphorylation in these cells. In addition, there is a selective increase in the pentose phosphate pathway in these cells resulting in ribose-5-phosphate to facilitate nucleotide synthesis to support cell proliferation.
Figure 3
Figure 3
Sirtuin expression in immune cells: The seven sirtuins SIRT1–7, the NAD+ sensors, are dispersed throughout subcellular compartments of cells. SIRT1 and SIRT6 are nuclear, SIRT7 is nucleolar, and SIRT3, SIRT4 and SIRT5 are localized in mitochondria, while SIRT2 is predominantly cytosolic. Each of these sirtuins have their own unique targets that define their biological activity as described in the text.
See this image and copyright information in PMC

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