2-Deoxyglucose and inflammation

Kellett, D. N.

doi:10.1111/j.2042-7158.1966.tb07853.x

Cited by 25 publications

(18 citation statements)

References 4 publications

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“…Inhibition of glycolysis with 2-DG blunts the inflammatory response in LPS-treated macrophages. Inhibitors of oxidative phosphorylation have no effect following LPS treatment, indicating that this process is already downregulated by LPS (46). IL-1β production in response to LPS treatment has been shown to be inhibited by 2-DG, and HIF1α has been implicated in this process (17,47).…”

Section: Hif1α and Immune-related Genesmentioning

confidence: 99%

HIF1α and metabolic reprogramming in inflammation

Corcoran¹,

O’Neill²

2016

Journal of Clinical Investigation

535

409

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Section: Hif1α and Immune-related Genesmentioning

confidence: 99%

HIF1α and metabolic reprogramming in inflammation

Corcoran¹,

O’Neill²

2016

Journal of Clinical Investigation

535

409

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“…We chose to address this question in macrophages because they are known to depend on glycolysis for energetic demands (16) and to produce most of their ATP through glycolysis (17,18). Although glycolytic inhibitors reduce both cellular ATP and effector functions of macrophages and neutrophils, inhibitors of mitochondrial respiration have little effect on these processes (19,20). In addition, an increase in glycolysis occurs in activated macrophages and is required for effector functions, including adhesion, extravasa- tion, motility, and invasion (21)(22)(23).…”

Section: Caspase-1 Activation During Salmonella Infection Leads To Thmentioning

confidence: 99%

The Caspase-1 Digestome Identifies the Glycolysis Pathway as a Target during Infection and Septic Shock

Shao

Yeretssian

Doiron

et al. 2007

Journal of Biological Chemistry

290

252

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Caspase-1 is an essential effector of inflammation, pyroptosis, and septic shock. Few caspase-1 substrates have been identified to date, and these substrates do not account for its wide range of actions. To understand the function of caspase-1, we initiated the systematic identification of its cellular substrates. Using the diagonal gel proteomic approach, we identified 41 proteins that are directly cleaved by caspase-1. Among these were chaperones, cytoskeletal and translation machinery proteins, and proteins involved in immunity. A series of unexpected proteins along the glycolysis pathway were also identified, including aldolase, triose-phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, ␣-enolase, and pyruvate kinase. With the exception of the latter, the identified glycolysis enzymes were specifically cleaved in vitro by recombinant caspase-1, but not caspase-3. The enzymatic activity of wild-type glyceraldehyde-3-phosphate dehydrogenase, but not a non-cleavable mutant, was dampened by caspase-1 processing. In vivo, stimuli that fully activated caspase-1, including Salmonella typhimurium infection and septic shock, caused a pronounced processing of these proteins in the macrophage and diaphragm muscle, respectively. Notably, these stimuli inhibited glycolysis in wildtype cells compared with caspase-1-deficient cells. The systematic characterization of caspase-1 substrates identifies the glycolysis pathway as a caspase-1 target and provides new insights into its function during pyroptosis and septic shock.Caspases are aspartate-specific cysteine proteases known for their function in regulating programmed cell death and inflammation. Phylogenetically, they are subdivided into the CED3-related enzymes that initiate and execute cell death and the caspase-1-related proteins that process and mature cytokines, viz. IL-1␤, 2 IL-18, and IL-33. Apoptotic caspases execute cell death through the restricted cleavage of key cellular proteins required to maintain cell viability, resulting in the morphological changes observed during apoptosis, including membrane blebbing, nuclear condensation, and cytoskeletal dismantling (1). Caspase-1 is essential during inflammation because of its role in the activation of cytokine signaling pathways. With the exception of its cytokine substrates, very little is known regarding the spectrum of cellular proteins it targets upon full activation. Similar to other caspases, caspase-1 is found in cells as an inactive precursor and is activated in response to inflammatory triggers, including pathogen-derived molecules, as well as danger signals released from infected or dying cells (2). Caspase-1 activation is achieved in a macromolecular complex known as the inflammasome through its recruitment to a scaffolding molecule generally via the adaptor ASC (3). Scaffolding molecules that activate caspase-1 within the inflammasome belong to the cytosolic Nod-like family of pathogen recognition receptors and include Nalp1-3, Ipaf, and Naip5 (4). More recently, a distinct caspase-1 activat...

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“…Unlike most cells, macrophages primarily generate ATP through glycolysis. 16,17 Moreover, macrophages increase the rate of glycolysis in response to Tolllike receptor (TLR) stimulation.…”

Section: Introductionmentioning

confidence: 99%

“…Unlike most cells, macrophages primarily generate ATP through glycolysis. 16,17 Moreover, macrophages increase the rate of glycolysis in response to Tolllike receptor (TLR) stimulation. 18 Previous attempts to measure ATP release from macrophages have yielded inconsistent results [19][20][21] that were likely complicated by endogenous CD39 activity.…”

Section: Introductionmentioning

confidence: 99%

TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses

Cohen

Briggs

Marino

et al. 2013

Blood

125

140

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• TLR-stimulated macrophages synthesize, release, and hydrolyze ATP via CD39 to regulate their own activation state.• The loss of macrophage CD39 prevents regulatory macrophage development and leads to lethal inflammatory responses and septic shock in mice.Sepsis is a highly fatal disease caused by an initial hyperinflammatory response followed by a state of profound immunosuppression. Although it is well appreciated that the initial production of proinflammatory cytokines by macrophages accompanies the onset of sepsis, it remains unclear what causes the transition to an immunosuppressive state. In this study, we reveal that macrophages themselves are key regulators of this transition and that the surface enzyme CD39 plays a critical role in self-limiting the activation process. We demonstrate that Toll-like receptor (TLR)-stimulated macrophages modulate their activation state by increasing the synthesis and secretion of adenosine triphosphate (ATP). This endogenous ATP is paradoxically immunosuppressive due to its rapid catabolism into adenosine by CD39. Macrophages lacking CD39 are unable to transition to a regulatory state and consequently continue to produce inflammatory cytokines. The importance of this transition is demonstrated in a mouse model of sepsis, where small numbers of CD39-deficient macrophages were sufficient to induce lethal endotoxic shock. Thus, these data implicate CD39 as a key "molecular switch" that allows macrophages to self-limit their activation state. We propose that therapeutics targeting the release and hydrolysis of ATP by macrophages may represent new ways to treat inflammatory diseases. (Blood. 2013;122(11):1935-1945 IntroductionFailure to control inflammatory macrophage activation responses can lead to pathological diseases, best exemplified by sepsis. Despite our growing understanding of its pathogenesis, sepsis continues to affect more than 200 000 people annually in the United States, with a mortality rate as high as 50%.1,2 The severe pathology associated with sepsis occurs in response to the hyperproduction of macrophagederived inflammatory cytokines, which can lead to vascular and tissue destruction, multiple organ failure, shock, and death.3 Intriguingly, macrophages isolated from late-stage septic individuals exhibit the phenotype of immunosuppressive, regulatory macrophages, expressing high levels of the anti-inflammatory cytokine interleukin-10 (IL-10) and low levels of tumor necrosis factor a (TNF-a) and IL-12. [4][5][6] These observations suggest the transition from inflammatory to immunosuppressive macrophages may be critical to control initial inflammatory responses and prevent lethal septic shock. 4,7,8 However, the molecular mechanism by which this transition is achieved remains poorly understood.In the present work, we examine the role that endogenous CD39 and adenosine triphosphate (ATP) play in regulating the macrophage inflammatory response. Recently, extracellular ATP (eATP) has been characterized as a "danger signal" that can promote inflammation through ...

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2-Deoxyglucose and inflammation

Cited by 25 publications

References 4 publications

HIF1α and metabolic reprogramming in inflammation

HIF1α and metabolic reprogramming in inflammation

The Caspase-1 Digestome Identifies the Glycolysis Pathway as a Target during Infection and Septic Shock

TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses

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