Abstract
The early initiation phase of acute inflammation is anabolic and primarily requires glycolysis with reduced mitochondrial glucose oxidation for energy, whereas the later adaptation phase is catabolic and primarily requires fatty acid oxidation for energy. We reported previously that switching from the early to the late acute inflammatory response following TLR4 stimulation depends on NAD(+) activation of deacetylase sirtuin 1 (SirT1). Here, we tested whether NAD(+) sensing by sirtuins couples metabolic polarity with the acute inflammatory response. We found in TLR4-stimulated THP-1 promonocytes that SirT1 and SirT 6 support a switch from increased glycolysis to increased fatty acid oxidation as early inflammation converts to late inflammation. Glycolysis enhancement required hypoxia-inducing factor-1α to up-regulate glucose transporter Glut1, phospho-fructose kinase, and pyruvate dehydrogenase kinase 1, which interrupted pyruvate dehydrogenase and reduced mitochondrial glucose oxidation. The shift to late acute inflammation and elevated fatty acid oxidation required peroxisome proliferator-activated receptor γ coactivators PGC-1α and β to increase external membrane CD36 and fatty acid mitochondrial transporter carnitine palmitoyl transferase 1. Metabolic coupling between early and late responses also required NAD(+) production from nicotinamide phosphoryltransferase (Nampt) and activation of SirT6 to reduce glycolysis and SirT1 to increase fatty oxidation. We confirmed similar shifts in metabolic polarity during the late immunosuppressed stage of human sepsis blood leukocytes and murine sepsis splenocytes. We conclude that NAD(+)-dependent bioenergy shifts link metabolism with the early and late stages of acute inflammation.
Highlights
Switching from the acute early initiation to late adaptation response after TLR4 stimulation depends on sirtuin 1 (SirT1)
We examined whether metabolism and inflammation are integrated in three ways: 1) inhibiting glucose uptake with 2-deoxyglucose, 2) blocking HIF-1␣ glycolysis by echinomycin, and 3) depleting RelB, the dual function transcription factor required for genespecific chromatin modifications associated with the adaptation phenotype in human sepsis and THP-1 cells [28]
This study reports for the first time, to our knowledge, that NADϩ-dependent processes couple metabolism with sequential early and late stages of the acute inflammatory response
Summary
Switching from the acute early initiation to late adaptation response after TLR4 stimulation depends on SirT1. Metabolic coupling between early and late responses required NAD؉ production from nicotinamide phosphoryltransferase (Nampt) and activation of SirT6 to reduce glycolysis and SirT1 to increase fatty oxidation. Innate and adaptive immune responses require a high energy state supported by glucose-dependent production of ATP and activation of NADPH oxidase to kill microorganisms by reactive oxygen species [3]. During this early stage of sepsis, precipitous decreases in ATP production by mitochondrial oxidative phosphorylation occur [4], and glycolysis provides the primary source of ATP [4, 5]. We recently reported that NADϩ informs deacetylase sirtuin 1 (SirT1) to
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