HIF1α and metabolic reprogramming in inflammation

Corcoran, Sarah E.; O’Neill, Luke A.J.

doi:10.1172/jci84431

Cited by 500 publications

(456 citation statements)

References 100 publications

(112 reference statements)

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“…These products, such as acetyl-CoA, NADH (nicotinamide adenine dinucleotide dehydrogenase) and FADH 2 (the fully reduced form of flavin adenine dinucleotide [FAD]), can be used in the TCA cycle and the electron transport chain to generate energy 2 . As discussed before, normoxia supports the TCA cycle and OXPHOS, while hypoxia via HIF-1α activation followed by the induction of glycolytic enzymes leads to glycolysis 2, 80 . The TCA cycle coupled to OXPHOS is the major metabolic pathway used by most quiescent or non-proliferating cells 2 .…”

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 78%

“…Most pyruvate is then excreted from the cells as lactate after a process called aerobic glycolysis. This is a relatively inefficient pathway for the generation of energy ( i.e ., cellular ATP) compared to the TCA cycle coupled to OXPHOS 80 . The preferential use of glycolysis versus the TCA cycle and OXPHOS depends on oxygen availability 2, 80 .…”

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

“…This is a relatively inefficient pathway for the generation of energy ( i.e ., cellular ATP) compared to the TCA cycle coupled to OXPHOS 80 . The preferential use of glycolysis versus the TCA cycle and OXPHOS depends on oxygen availability 2, 80 . Glycolysis is favored during hypoxia, a situation encountered, for instance, in joints during rheumatoid arthritis or in the inflamed colon during Crohn’s disease 80 - PDC can be present in both inflamed tissues ( i.e ., the synovial fluid 81– 83 and the colon 73, 84 ).…”

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

“…The preferential use of glycolysis versus the TCA cycle and OXPHOS depends on oxygen availability 2, 80 . Glycolysis is favored during hypoxia, a situation encountered, for instance, in joints during rheumatoid arthritis or in the inflamed colon during Crohn’s disease 80 - PDC can be present in both inflamed tissues ( i.e ., the synovial fluid 81– 83 and the colon 73, 84 ). This energy provided by glycolysis may represent the resources necessary for cytokine secretion, since PDC does not proliferate in the same way as adaptive cells ( i.e ., T cells).…”

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

“…Indeed, HIF-1α is critical for glycolysis to generate ATP, since it induces the expression of different glycolytic enzymes, such as hexokinase and phosphofructokinase 80 . In addition to HIF-1α activation, the TLR7 agonist gardiquimod, as well as Flu and RV, induces early glycolysis (within minutes) in human PDC, as attested by elevated extracellular acidification rate (ECAR; a reflection of lactate secretion in extracellular milieu, an indicator of glycolysis in real time) and elevated rates of lactate production 4 .…”

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

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Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

Saas¹,

Varin²,

Perruche³

et al. 2017

F1000Res

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There are more and more data concerning the role of cellular metabolism in innate immune cells, such as macrophages or conventional dendritic cells. However, few data are available currently concerning plasmacytoid dendritic cells (PDC), another type of innate immune cells. These cells are the main type I interferon (IFN) producing cells, but they also secrete other pro-inflammatory cytokines (e.g., tumor necrosis factor or interleukin [IL]-6) or immunomodulatory factors (e.g., IL-10 or transforming growth factor-β). Through these functions, PDC participate in antimicrobial responses or maintenance of immune tolerance, and have been implicated in the pathophysiology of several autoimmune diseases. Recent data support the idea that the glycolytic pathway (or glycolysis), as well as lipid metabolism (including both cholesterol and fatty acid metabolism) may impact some innate immune functions of PDC or may be involved in these functions after Toll-like receptor (TLR) 7/9 triggering. Some differences may be related to the origin of PDC (human versus mouse PDC or blood-sorted versus FLT3 ligand stimulated-bone marrow-sorted PDC). The kinetics of glycolysis may differ between human and murine PDC. In mouse PDC, metabolism changes promoted by TLR7/9 activation may depend on an autocrine/paracrine loop, implicating type I IFN and its receptor IFNAR, explaining a delayed glycolysis. Moreover, PDC functions can be modulated by the metabolism of cholesterol and fatty acids. This may occur via the production of lipid ligands that activate nuclear receptors (e.g., liver X receptor [LXR]) in PDC or through limiting intracellular cholesterol pool size (by statins or LXR agonists) in these cells. Finally, lipid-activated nuclear receptors ( i.e., LXR or peroxisome proliferator activated receptor) may also directly interact with pro-inflammatory transcription factors, such as NF-κB. Here, we discuss how glycolysis and lipid metabolism may modulate PDC functions and how this may be harnessed in pathological situations where PDC play a detrimental role.

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Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 78%

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

Section: The Influence Of the Metabolism On Innate Immune Functionmentioning

confidence: 99%

See 3 more Smart Citations

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

Saas¹,

Varin²,

Perruche³

et al. 2017

F1000Res

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Krebs cycle rewired for macrophage and dendritic cell effector functions

2017

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Edited by Laszlo NagyThe Krebs cycle is an amphibolic pathway operating in the mitochondrial matrix of all eukaryotic organisms. In response to proinflammatory stimuli, macrophages and dendritic cells undergo profound metabolic remodelling to support the biosynthetic and bioenergetic requirements of the cell. Recently, it has been discovered that this metabolic shift also involves the rewiring of the Krebs cycle to regulate cellular metabolic flux and the accumulation of Krebs cycle intermediates, notably, citrate, succinate and fumarate. Interestingly, a new role for Krebs cycle intermediates as signalling molecules and immunomodulators that dictate the inflammatory response has begun to emerge. This review will discuss the latest developments in Krebs cycle rewiring and immune cell effector functions, with a particular focus on the regulation of cytokine production.

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Macrophage metabolism in atherosclerosis

2017

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A key aspect of atherosclerosis is the maladaptive inflammatory response to lipoprotein accumulation in the artery. The failure to decrease lipid accumulation, to clear apoptotic cells, and to resolve inflammation ultimately leads to macrophage accumulation within the vascular wall [Thorp EB (2010) Apoptosis 15, 1124–1136; Moore K et al. (2013) Nat Rev Immunol 13, 709–721; Moore KJ and Tabas I (2011) Cell 145, 341–355; Ley K et al. (2011) Arterioscler Thromb Vasc Biol 31, 1506–1516]. Several subsets of macrophages are found inside atherosclerotic plaques [Chinetti‐Gbaguidi G et al. (2015) Nat Rev Cardiol 12, 10–17; Leitinger N and Schulman IG (2013) Arterioscler Thromb Vasc Biol 33, 1120–1126; Mantovani A et al. (2009) Arterioscler Thromb Vasc Biol 29, 1419–1423]: Proinflammatory M1‐like macrophages potentially participate in atherosclerosis initiation and progression; M2‐like macrophages are thought to be protective due to their anti‐inflammatory and profibrotic properties, presumably stabilizing the plaque [Chistiakov DA et al. (2015) Int J Cardiol 184, 436–445; Gordon S (2003) Nat Rev Immunol 3, 23–35]; Mox macrophages develop in response to oxidized phospholipids and present a glutathione‐ and potentially redox‐regulating phenotype [Kadl A et al. (2010) Circ Res 107, 737–746]; Mhem macrophages are found in areas of plaque hemorrhage [Boyle JJ et al. (2009) Am J Pathol 174, 1097–1108; Boyle JJ et al. (2012) Circ Res 110, 20–33] where they are involved in heme clearance. Recent evidence suggests that the relative abundance of these macrophage subsets is a better indicator of plaque progression and stability than the total number of lesion macrophages [Chinetti‐Gbaguidi G et al. (2015) Nat Rev Cardiol 12, 10–17]. Over the last few years, findings in the area of immunometabolism established a link between the metabolic state of the different macrophage phenotypes and their functions [O'Neill LAJ and Pearce EJ (2016) J Exp Med 213, 15–23]. However, the effect of metabolic changes in macrophages on atherosclerotic plaque progression and stability is not well understood and an area of intensive study. In this review, we will summarize and critically discuss recent developments in the field of macrophage metabolism in the context of atherosclerosis to guide future investigation in this area.

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HIF1α and metabolic reprogramming in inflammation

Cited by 500 publications

References 100 publications

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

Krebs cycle rewired for macrophage and dendritic cell effector functions

Macrophage metabolism in atherosclerosis

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