Glycolysis and Inflammation: Partners in Crime!

HomeCirculation ResearchVol. 129, No. 1Glycolysis and Inflammation: Partners in Crime! Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBGlycolysis and Inflammation: Partners in Crime! Ralf P. Brandes and Flávia Rezende Ralf P. BrandesRalf P. Brandes Correspondence to: Ralf P. Brandes, MD, Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern Kai 7, 60590 Frankfurt am Main. Email E-mail Address: [email protected] https://orcid.org/0000-0002-8035-0048 Institute for Cardiovascular Physiology, Faculty of Medicine, Goethe-University Frankfurt, Germany (R.P.B., F.R.). DZHK – German Center for Cardiovascular Research, Partner site Rhine-Main (R.P.B., F.R.). Search for more papers by this author and Flávia RezendeFlávia Rezende Institute for Cardiovascular Physiology, Faculty of Medicine, Goethe-University Frankfurt, Germany (R.P.B., F.R.). DZHK – German Center for Cardiovascular Research, Partner site Rhine-Main (R.P.B., F.R.). Search for more papers by this author Originally published24 Jun 2021https://doi.org/10.1161/CIRCRESAHA.121.319447Circulation Research. 2021;129:30–32This article is a commentary on the followingImmunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose MetabolismArticle, see p 9From the point of view of an endothelial cell, inflammation represents a most important change in the cellular microenvironment, which necessitates an immediate and profound response. The heterogeneity of the resting endothelium, which facilitates the fine-tuned response of this cellular compartment to the physio-chemical environment, is given up for the sake of a stereotypic inflammatory program.1 The abrupt change in the endothelial phenotype appears meaningful considering that the endothelium forms the central part of the vascular barrier: It controls recruitment of inflammatory cells, permeability, and local nutrient delivery. Inflammatory stimuli like the cytokine TNFα (tumor necrosis factor α) or ligands to TLRs (toll-like receptor) like lipopolysaccharide elicit this response by the stimulation of numerous signal transduction cascades, resulting in the activation of a range of different transcription factors. Among them are NFκB (nuclear factor kappa B), HIF1 (hypoxia-inducible factor 1),2 NRF2 (nuclear factor erythroid 2-related factor 2), AP-1 (activator protein 1), and STAT (signal transducer and activator of transcription) factors. As a consequence, inflammation not only induces immediate early genes, it also leads to substantial epigenetic chromatin changes, with profound consequences for the cellular phenotype.3In this issue of Circulation Research, Xiao et al4 report that inflammatory stimuli increase endothelial cell glucose utilization through increasing glycolysis and pentose phosphate cycle. Also, endothelial lactate release was increased, documenting that during inflammation, endothelial cells favor ATP production through glycolysis over oxidative phosphorylation in mitochondria. This observation confirms the notion that activated endothelial cells, also during proliferation, exhibit high glycolytic activity,5 which is explained by 3 different arguments: (1) activated endothelial cells in the setting of angiogenesis, should have the capacity to invade hypoxic areas and thus therefore not be oxygen-dependent, (2) high endothelial oxygen consumption would limit oxygen supply to the target tissue, and (3) the high endothelial NO production results in mitochondrial complex IV inactivation and thus necessitates ATP production by glycolysis.6 Inflammation and hypoxia are both situations of increased NO production and thus mitochondrial respiratory chain inactivation. Even on the level of transcription factors, it is well appreciated that inflammatory stimuli elicit a pseudo hypoxic response by inducing and stabilizing the transcription factor HIF1α. Importantly, HIF reprograms cells towards anaerobic glycolysis and also promotes inflammatory gene expression.7With respect to metabolic reprogramming by inflammatory stimuli, the work of Xaio et al,4 therefore, extends existing concepts by adding specific molecular targets, among them the transcription factor FoxO1 (forkhead box protein O1) and the FoxO1-PDK4 (pyruvate dehydrogenase lipoamide kinase isozyme 4) axis which are downregulated in response to inflammation. What, however, makes the present study particularly interesting is that the metabolic reprogramming of endothelial cells towards glycolysis promotes the inflammatory response. Mechanistically, inflammation through NFκB (and probably other transcription factors) induces PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform-3),4 a key control enzyme of glycolysis.5 Inhibition of glycolysis or downregulation of PFKFB3 attenuated endothelial inflammatory gene expression and monocyte adhesion, whereas overexpression of PFKFB3 had the opposite effect. Based on this and other findings, the authors conclude that glycolysis promotes the endothelial inflammatory response (Figure). The exact nature of this interaction, however, remains somewhat unclear as Xiao et al4 focus largely on indirect mechanisms: they report that energy production by mitochondria as compared to glycolysis is rather anti-inflammatory. Moreover, an important interplay exists between glycolysis and pentose phosphate cycle, where both compete for glucose. The pentose phosphate cycle is a main source of NADPH and thus of the cellular antioxidant defense system. Oxidative stress is a proinflammatory situation as reactive oxygen species activate numerous pathways like tyrosine kinases and MAP kinases (mitogen activated protein kinases) resulting in NFκB, AP-1, and HIF signaling.8 A reduced pentose phosphate cycle activity, as consequence of increased flux of glucose towards glycolysis, or oxidative inactivation of G6PDH (glucose 6-phosphate dehydrogenase) should, therefore, support inflammation.Download figureDownload PowerPointFigure. Endothelial positive feedback loop between glycolysis and inflammation. Inflammation activates numerous transcription factors, among them NFκB (nuclear factor kappa B), HIF1 (hypoxia-inducible factor 1), and NRF2 (nuclear factor erythroid 2-related factor 2), which promote PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform-3) expression and glycolytic activity. Glycolysis, potentially through reactive aldehydes and a redox-dependent mechanism exerts a positive feedback on the inflammatory transcription factors.Is it possible that intermediates of the glycolysis directly promote inflammation? Lactate, for example, has recently been shown to modify histones through lactylation to change macrophage gene expression.9 Moreover, intermediates of the glycolysis, like dihydroxyacetone phosphate and glyceraldehyde-3-phosphatase give rise to reactive aldehydes,10,11 which may induce an oxidant stress-dependent inflammatory response (Figure). Without a detailed deconvolution and time-resolved determination of the levels of the different metabolites in conjunction with gene expression, a more detailed analysis of the complex interplay between metabolism and inflammatory gene expression is hardly possible. This aspect represents a potential weakness by the study of Xiao et al4 as analyses were mainly carried out for the late time point 24 hours after cytokine stimulation. Given that several of the readouts used, like VCAM1 (vascular cell adhesion molecule 1) or E-selectin are induced by cytokines within minutes, such a late time point is difficult to interpret in particular as some of the effects of metabolic reprogramming on inflammatory gene expression were rather modest. It is, therefore, assuring that the authors also could provide some in vivo evidence, largely based on pharmacological inhibitors, to support their cell culture findings.An interesting side question of the present study was how cytokines and metabolism elicit oxidative stress to promote inflammatory gene expression. TNFα and lipopolysaccharide have been linked to mitochondrial reactive oxygen species (ROS) as well as to the NADPH oxidases Nox1 and Nox2.8 Nox4, in contrast, through H2O2 production is thought to rather stabilized a quiescent endothelial phenotype 12,13. In keeping with this concept, Nox4 mRNA expression was not induced by cytokines in the present study, and inhibition of G6PDH further suppressed Nox4. The authors interpret the latter aspect as an attempt of the cell to balance its redox network: Nox enzymes, as well as NO synthase and the cellular antioxidant defense all depend on NADPH. Although this aspect is an interesting consideration, whether or not there is true competition for substrate among the systems is unclear. The flux rates for the individual pathways are not well established and have not been determined during cytokine stimulation. In fact, there are very few studies to suggest that lowering G6PDH activity decreases oxidative stress by limiting NADPH supply to Nox enzymes.14In conclusion, the work by Xiao et al4 unravels a complex interdependency of inflammation and glucose utilization in endothelial cells. Whereas pentose phosphate cycle and mitochondrial glucose utilization limit the inflammatory response of endothelial cells, glycolysis rather promotes inflammation.Source of FundingThis work was supported by the Goethe University Frankfurt am Main, the Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) the Deutsche Forschungsgemeinschaft (DFG) excellence cluster EXS2026 Cardiopulmonary System CPI and the DFG Sonderforschungsbereich 834 (Teilprojekt A2 to R.P. Brandes) and DFG RE 4360/2-1 to F. Rezende.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 32.Correspondence to: Ralf P. Brandes, MD, Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität, Theodor-Stern Kai 7, 60590 Frankfurt am Main. Email [email protected]uni-frankfurt.deReferences1. Kaur H, Carvalho J, Looso M, Singh P, Chennupati R, Preussner J, Günther S, Albarrán-Juárez J, Tischner D, Classen S, et al.. Single-cell profiling reveals heterogeneity and functional patterning of GPCR expression in the vascular system.Nat Commun. 2017; 8:15700. doi: 10.1038/ncomms15700CrossrefMedlineGoogle Scholar2. Frede S, Stockmann C, Freitag P, Fandrey J. Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB.Biochem J. 2006; 396:517–527. doi: 10.1042/BJ20051839CrossrefMedlineGoogle Scholar3. 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Glucose-6-phosphate dehydrogenase deficiency decreases vascular superoxide and atherosclerotic lesions in apolipoprotein E(-/-) mice.Arterioscler Thromb Vasc Biol. 2006; 26:910–916. doi: 10.1161/01.ATV.0000205850.49390.3bLinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesImmunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose MetabolismWusheng Xiao, et al. Circulation Research. 2021;129:9-29 June 25, 2021Vol 129, Issue 1Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.121.319447PMID: 34166079 Originally publishedJune 24, 2021 Keywordshypoxiaoxidative stressglycolysisinflammationEditorialsPDF download Advertisement