Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation

Krawczyk, Connie M.; Holowka, Thomas; Sun, Jie; Blagih, Julianna; Amiel, Eyal; DeBerardinis, Ralph J.; Cross, Justin R.; Jung, Euihye; Thompson, Craig B.; Jones, Russell G.; Pearce, Edward J.

doi:10.1182/blood-2009-10-249540

Cited by 1,046 publications

(1,246 citation statements)

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“…Warburg went on to conclude, however, in 1958 that this "cancer metabolism" did not occur in leukocytes, his opinion being that the observation of aerobic glycolysis in these cells was an artifact of preparation (10). This proved to be an incorrect conclusion because we now know that a switch in metabolism from oxidative phosphorylation to glycolysis occurs following activation of macrophages and dendritic cells (DCs) by LPS (6,11), in a similar manner to the Warburg effect observed in tumor cells (9). A metabolomic screen and microarray analysis in macrophages activated by LPS have confirmed this switch from oxidative phosphorylation to glycolysis.…”

Section: The Warburg Effect In Activated Macrophagesmentioning

confidence: 97%

“…LPS has been shown to decrease AMPK activation, whereas activation of AMPK results in a decrease in NF-B activation and TNF␣ production in macrophages following stimulation with inflammatory stimuli such as LPS (45). Knockdown of AMPK enhances LPS-induced IL-12p40 expression in DCs (11). AMPK-␣1 Ϫ/Ϫ mice are more prone to severe experimental autoimmune encephalomyelitis in comparison with controls, whereas spleen cells isolated from these mice secrete more IFN␥ and less IL-17 following antigen stimulation.…”

Section: Role Of Nad ؉ Sirtuins and Amp-dependent Protein Kinase Imentioning

confidence: 99%

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How Metabolism Generates Signals during Innate Immunity and Inflammation

McGettrick

O’Neill

2013

Journal of Biological Chemistry

204

167

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The interplay between immunity, inflammation, and metabolic changes is a growing field of research. Toll-like receptors and NOD-like receptors are families of innate immune receptors, and their role in the human immune response is well documented. Exciting new evidence is emerging with regard to their role in the regulation of metabolism and the activation of inflammatory pathways during the progression of metabolic disorders such as type 2 diabetes and atherosclerosis. The proinflammatory cytokine IL-1␤ appears to play a central role in these disorders. There is also evidence that metabolites such as NAD ؉ (acting via deacetylases such as SIRT1 and SIRT2) and succinate (which regulates hypoxia-inducible factor 1␣) are signals that regulate innate immunity. In addition, the extracellular overproduction of metabolites such as uric acid and cholesterol crystals acts as a signal sensed by NLRP3, leading to the production of IL-1␤. These observations cast new light on the role of metabolism during host defense and inflammation.

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Section: The Warburg Effect In Activated Macrophagesmentioning

confidence: 97%

Section: Role Of Nad ؉ Sirtuins and Amp-dependent Protein Kinase Imentioning

confidence: 99%

How Metabolism Generates Signals during Innate Immunity and Inflammation

McGettrick

O’Neill

2013

Journal of Biological Chemistry

204

167

View full text Add to dashboard Cite

show abstract

“…It is now clear that acute and chronic inflammatory responses can add to the total tissue injury that occurs, making it important to identify how it is regulated. Complex interactions are occurring between inflammation and metabolism, and their importance is increasingly appreciated with the identification of mechanistic pathways (10,27,29). One aspect of this interrelationship is the change in metabolism that occurs with the initiation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Farooq

Hoque

Ouyang

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Farooq A, Hoque R, Ouyang X, Farooq A, Ghani A, Ahsan K, Guerra M, Mehal WZ. Activation of N-methyl-D-aspartate receptor downregulates inflammasome activity and liver inflammation via a ␤-arrestin-2 pathway. Am J Physiol Gastrointest Liver Physiol 307: G732-G740, 2014. First published August 7, 2014; doi:10.1152/ajpgi.00073.2014.-Activation of the cytosolic inflammasome machinery is responsible for acute and chronic liver inflammation, but little is known about its regulation. The N-methyl-Daspartate (NMDA) receptor families are heterotetrameric ligand-gated ion channels that are activated by a range of metabolites, including aspartate, glutamate, and polyunsaturated fatty acids. In the brain NMDA receptors are present on neuronal and nonneuronal cells and regulate a diverse range of functions. We tested the role of the NMDA receptor and aspartate in inflammasome regulation in vitro and in models of acute hepatitis and pancreatitis. We demonstrate that the NMDA receptor is present on Kupffer cells, and their activation on primary mouse and human cells limits inflammasome activation by downregulating NOD-like receptor family, pyrin domain containing 3 and procaspase-1. The NMDA receptor pathway is active in vivo, limits injury in acute hepatitis, and can be therapeutically further activated by aspartate providing protection in acute inflammatory liver injury. Downregulation of inflammasome activation by NMDA occurs via a ␤-arrestin-2 NF-k␤ and JNK pathway and not via Ca 2ϩ mobilization. We have identified the NMDA receptor as a regulator of inflammasome activity in vitro and in vivo. This has identified a new area of immune regulation associated by metabolites that may be relevant in a diverse range of conditions, including nonalcoholic steatohepatitis and total parenteral nutrition-induced immune suppression.aspartate

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“…In recent years it has become evident that immune cells have the ability to shift their metabolism under varying conditions and that this is essential for proper immune function [2]. Stimulation of DCs and macrophages can result in a decrease in oxidative phosphorylation, which is normally employed under resting conditions, with a concomitant increase in glycolysis and the pentose-phosphate pathway [3,4]. This switch to glycolysis rapidly generates ATP to maintain mitochondrial membrane potential and energy homeostasis, ultimately ensuring cell viability [5].…”

mentioning

confidence: 99%

Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

553

445

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Succinate is an intermediate of the tricarboxylic acid (TCA) cycle, and plays a crucial role in adenosine triphosphate (ATP) generation in mitochondria. Recently, new roles for succinate outside metabolism have emerged. Succinate stabilizes the transcription factor hypoxia-inducible factor-1a (HIF-1a) in specific tumors and in activated macrophages, and stimulates dendritic cells via its receptor succinate receptor 1. Furthermore, succinate has been shown to post-translationally modify proteins. This expanding repertoire of functions for succinate suggests a broader role in cellular activation. We review the new roles of succinate and draw parallels to other metabolites such as NAD + and citrate whose roles have expanded beyond metabolism and into signaling. Metabolic alterations influence the immune responseThe immune system acts as an internal shield defending against invading pathogens and is made up of an innate system, including macrophages, neutrophils, and dendritic cells (DCs), and an adaptive system composed of T and B lymphocytes. Cells of the innate immune system recognize pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), present on their cell surface and in the cytosol [1]. Once activated, innate immune cells can initiate adaptive immunity to fight infection further and to generate immunological memory. In resting conditions these cells are relatively inactive; however, upon recognition of foreign material they have the ability to respond rapidly, producing a wide array of mediators such as cytokines, chemokines, and antimicrobial peptides to clear the infection.Such rapid induction of immunity represents a significant metabolic demand. In recent years it has become evident that immune cells have the ability to shift their metabolism under varying conditions and that this is essential for proper immune function [2]. Stimulation of DCs and macrophages can result in a decrease in oxidative phosphorylation, which is normally employed under resting conditions, with a concomitant increase in glycolysis and the pentose-phosphate pathway [3,4]. This switch to glycolysis rapidly generates ATP to maintain mitochondrial membrane potential and energy homeostasis, ultimately ensuring cell viability [5]. It also provides biosynthetic precursors required for proliferating cells and for cells with a prodigious biosynthetic capacity, such as macrophages when they are activated to produce cytokines. This altered metabolism is similar to the Warburg effect (aerobic glycolysis) observed in tumor cells [6] (Figure 1, Box 1). Indeed, the metabolic sensor HIF-1a can determine the growth and fate of both tumor cells and immune cells. For example, HIF-1a activation favors differentiation of T lymphocytes into proinflammatory Th17 cells and attenuates regulatory T cell development [7]. Importantly, as well as global changes in metabolism that occur in activated immune cells, individual metabolites, including succinate, citrate, and NAD + , have been d...

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Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation

Cited by 1,046 publications

References 40 publications

How Metabolism Generates Signals during Innate Immunity and Inflammation

How Metabolism Generates Signals during Innate Immunity and Inflammation

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Succinate: a metabolic signal in inflammation

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