How Metabolism Generates Signals during Innate Immunity and Inflammation

McGettrick, Anne F.; O’Neill, Luke A. J.

doi:10.1074/jbc.r113.486464

Cited by 197 publications

(171 citation statements)

References 54 publications

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“…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 demonstrated to possess signaling capacity and to influence immunity [4,8,9]. These somewhat surprising findings allow for metabolic changes occurring in inflammatory cells to serve as signals to which cells respond and can contribute to the inflammatory process ( Figure 2).…”

Section: Metabolic Alterations Influence the Immune Responsementioning

confidence: 99%

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Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

515

434

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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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Section: Metabolic Alterations Influence the Immune Responsementioning

confidence: 99%

“…Sirt1-dependent PGC-1b activation increases oxidative phosphorylation, and this may contribute to a net antiinflammatory effect by decreasing the number of damaged mitochondria and subsequent ROS production [9].…”

Section: Box 1 the Relationship Between Succinate And Hif-1a In Cancermentioning

confidence: 99%

Succinate: a metabolic signal in inflammation

Mills

O’Neill

2014

Trends in Cell Biology

515

434

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“…Macrophage activation in innate immunity causes a shift in metabolism toward glycolysis (23,24). This event is hypoxiainducible factor-1α (HIF-1α)-dependent, with HIF-1α also being needed for induction of HIF-1α-dependent genes, including those encoding IL-1β.…”

Section: Significancementioning

confidence: 99%

Trypanosoma bruceimetabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The parasite Trypanasoma brucei causes African trypanosomiasis, known as sleeping sickness in humans and nagana in domestic animals. These diseases are a major burden in the 36 sub-Saharan African countries where the tsetse fly vector is endemic. Untreated trypanosomiasis is fatal and the current treatments are stagedependent and can be problematic during the meningoencephalitic stage, where no new therapies have been developed in recent years and the current drugs have a low therapeutic index. There is a need for more effective treatments and a better understanding of how these parasites evade the host immune response will help in this regard. The bloodstream form of T. brucei excretes significant amounts of aromatic ketoacids, including indolepyruvate, a transamination product of tryptophan. This study demonstrates that this process is essential in bloodstream forms, is mediated by a specialized isoform of cytoplasmic aminotransferase and, importantly, reveals an immunomodulatory role for indolepyruvate. Indolepyruvate prevents the LPS-induced glycolytic shift in macrophages. This effect is the result of an increase in the hydroxylation and degradation of the transcription factor hypoxia-inducible factor-1α (HIF-1α). The reduction in HIF-1α levels by indolepyruvate, following LPS or trypanosome activation, results in a decrease in production of the proinflammatory cytokine IL-1β. These data demonstrate an important role for indolepyruvate in immune evasion by T. brucei.immunometabolism | innate immunity | immune evasion |

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“…For example, it is now clear that the shift from mitochondrial oxidative phosphorylation to glycolysis in innate immune cells is crucial in providing the energy and signals for producing pro-inflammatory cytokines and other host defense proteins during infection [105]. Metabolites such as succinate and citrate have a direct effect on the functioning of immune cells such as macrophages and dendritic cells [106].…”

Section: Bmal1-a Master Regulatormentioning

confidence: 99%