Background: Switching from the acute early initiation to late adaptation response after TLR4 stimulation depends on SirT1. Results: Switching from glucose to fatty acid oxidation between initiation and adaptation responses requires SirT6 and SirT1. Conclusion: Bioenergy integrates metabolism and acute inflammation. Significance: Understanding bioenergy shifts during inflammation may enable development of new therapies.

Gene-selective epigenetic reprogramming and shifts in cellular bioenergetics develop when Toll-like receptors (TLR) recognize and respond to systemic life-threatening infections. Using a human monocyte cell model of endotoxin tolerance and human leukocytes from acute systemic inflammation with sepsis, we report that energy sensor sirtuin 1 (SIRT1) coordinates the epigenetic and bioenergy shifts. After TLR4 signaling, SIRT1 rapidly accumulated at the promoters of TNF-␣ and IL-1␤, but not IB␣; SIRT1 promoter binding was dependent on its co-factor, NAD ؉ . During this initial process, SIRT1 deacetylated RelA/ p65 lysine 310 and nucleosomal histone H4 lysine 16 to promote termination of NFB-dependent transcription. SIRT1 then remained promoter bound and recruited de novo induced RelB, which directed assembly of the mature transcription repressor complex that generates endotoxin tolerance. SIRT1 also promoted de novo expression of RelB. During sustained endotoxin tolerance, nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme for endogenous production of NAD ؉ , and SIRT1 expression increased. The elevation of SIRT1 required protein stabilization and enhanced translation. To support the coordination of bioenergetics in human sepsis, we observed elevated NAD ؉ levels concomitant with SIRT1 and RelB accumulation at the TNF-␣ promoter of endotoxin tolerant sepsis blood leukocytes. We conclude that TLR4 stimulation and human sepsis activate pathways that couple NAD ؉ and its sensor SIRT1 with epigenetic reprogramming.Two cellular processes predictably accompany TLR-mediated acute systemic inflammation caused by sepsis, a highly destructive and often lethal process. The first process occurs when epigenetic alterations reprogram distinct functional sets of genes to both activate and repress transcription of hundreds of genes (1, 2); this transcriptome reprogramming generates the phenomenon known as endotoxin tolerance (3). Endotoxin tolerance requires TLR 3 receptor signaling of NFB master regulator, which first induces and then represses rapid response and potentially autotoxic proinflammatory TNF-␣ and IL-1␤. To control the initial recognition and response phases induced by TLR, gene-specific reprogramming selectively modifies chromatin structure and shifts nucleosomes on responsive euchromatin to form silent heterochromatin at acute proinflammatory genes; in contrast, genes encoding anti-inflammatory and antimicrobial mediators maintain responsive euchromatin (4, 5). This gene set-selective reprogramming generates a clinically relevant phenotypic transition from the hyperinflammatory to the hypoinflammatory endotoxin tolerant state, which may last hours, days, or weeks, depending on the strength of the initial TLR response (4, 5). The physiologic importance of endotoxin tolerance is still incompletely understood, but likely reflects an attempt to recover homeostasis (3).Others and we (6 -9) reported how temporal transitions in epigenetic programming alter the course of acute inflammation. NFB master ...

Mechanism-based sepsis treatments are unavailable, and their incidence is rising worldwide. Deaths occur during the early acute phase of hyperinflammation or subsequent postacute hypoinflammatory phase with sustained organ failure. The acute sepsis phase shifts rapidly, and multiple attempts to treat early excessive inflammation have uniformly failed. We reported in a sepsis cell model and human sepsis blood leukocytes that nuclear NAD+ sensor SIRT1 deacetylase remodels chromatin at specific gene sets to switch the acute-phase proinflammatory response to hypoinflammatory. Importantly, SIRT1 chromatin reprogramming is reversible, suggesting that inhibition of SIRT1 might reverse postacute-phase hypoinflammation. We tested this concept in septic mice, using the highly specific SIRT1 inhibitor EX-527, a small molecule that closes the NAD+ binding site of SIRT1. Strikingly, when administered 24 h after sepsis, all treated animals survived, whereas only 40% of untreated mice survived. EX-527 treatment reversed the inability of leukocytes to adhere at the small intestine MVI, reversed in vivo endotoxin tolerance, increased leukocyte accumulation in peritoneum, and improved peritoneal bacterial clearance. Mechanistically, the SIRT1 inhibitor restored repressed endothelial E-selectin and ICAM-1 expression and PSGL-1 expression on the neutrophils. Systemic benefits of EX-527 treatment included stabilized blood pressure, improved microvascular blood flow, and a shift toward proimmune macrophages in spleen and bone marrow. Our findings reveal that modifying the SIRT1 NAD+ axis may provide a novel way to treat sepsis in its hypoinflammatory phase.

Background: Nuclear SIRT1 and SIRT6 switch monocyte energy sources from glycolysis to fatty acid oxidation during sepsis adaptation. Results: Sequential actions of nuclear SIRT1 and RELB differentially induce SIRT3 expression and increase mitochondrial biogenesis during sepsis adaptation. Conclusion: SIRT1 and RELB link nuclear and mitochondrial alterations in bioenergetics during sepsis. Significance: Communication between nuclear and mitochondrial functions may influence sepsis outcomes.

We review the emerging concept that changes in cellular bioenergetics concomitantly reprogram inflammatory and metabolic responses. The molecular pathways of this integrative process modify innate and adaptive immune reactions associated with inflammation, as well as influencing the physiology of adjacent tissue and organs. The initiating proinflammatory phase of inflammation is anabolic and requires glucose as the primary fuel, whereas the opposing adaptation phase is catabolic and requires fatty acid oxidation. The fuel switch to fatty acid oxidation depends on the sensing of AMP and NAD(+) by AMPK and the SirT family of deacetylases (e.g., SirT1, -6, and -3), respectively, which couple inflammation and metabolism by chromatin and protein reprogramming. The AMP-AMPK/NAD(+)-SirT axis proceeds sequentially during acute systemic inflammation associated with sepsis but ceases during chronic inflammation associated with diabetes, obesity, and atherosclerosis. Rebalancing bioenergetics resolves inflammation. Manipulating cellular bioenergetics is identifying new ways to treat inflammatory and immune diseases.

The goal of this investigation was to define the molecular mechanism underlying physiologic conversion of immune tolerance to resolution of the acute inflammatory response, which is unknown. An example of this knowledge gap and its clinical importance is the broad-based energy deficit and immunometabolic paralysis in blood monocytes from non-survivors of human and mouse sepsis that precludes sepsis resolution. This immunometabolic dysregulation is biomarked by ex vivo endotoxin tolerance to increased glycolysis and TNF-α expression. To investigate how tolerance switches to resolution, we adapted our previously documented models associated with acute inflammatory, immune, and metabolic reprogramming that induces endotoxin tolerance as a model of sepsis in human monocytes. We report here that mitochondrial sirtuin 4 (SIRT4) physiologically breaks tolerance and resolves acute inflammation in human monocytes by coordinately reprogramming of metabolism and bioenergetics. We find that increased SIRT4 mRNA and protein expression during immune tolerance counters the increase in pyruvate dehydrogenase kinase 1 (PDK1) and SIRT1 that promote tolerance by switching glucose-dependent support of immune resistance to fatty acid oxidation support of immune tolerance. By decreasing PDK1, pyruvate dehydrogenase complex reactivation rebalances mitochondrial respiration, and by decreasing SIRT1, SIRT4 represses fatty acid oxidation. The precise mechanism for the mitochondrial SIRT4 nuclear feedback is unclear. Our findings are consistent with a new concept in which mitochondrial SIRT4 directs the axis that controls anabolic and catabolic energy sources.

NAD(+)-dependent deacetylase SIRT1 is a master regulator of nucleosome positioning and chromatin structure, thereby reprogramming gene expression. In acute inflammation, chromatin departs from, and returns to, homeostasis in an orderly sequence. This sequence depends on shifts in NAD(+) availability for SIRT1 activation and deacetylation of signaling proteins, which support orderly gene reprogramming during acute inflammation by switching between euchromatin and heterochromatin. In contrast, in chronic inflammation and cancer, limited availability of NAD(+) and reduced expression of SIRT1 may sustain aberrant chromatin structure and functions. SIRT1 also influences inflammation and cancer by directly deacetylating targets like NFκB p65 and p53. Here, we review SIRT1 in the context of inflammation and cancer.

BackgroundTranscriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret.ResultsUsing transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55–94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR ≤ 0.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p < 0.05). Lastly, 15 genes with age-associated expression were also associated (FDR ≤ 0.01) with pulse pressure independent of chronological age.Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n = 423) of the population, we identified 30 age-associated (FDR < 0.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types.ConclusionsAn overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1522-4) contains supplementary material, which is available to authorized users.