GM-CSF Enhances Macrophage Glycolytic Activity In Vitro and Improves Detection of Inflammation In Vivo

Singh, Parmanand; González-Ramos, Silvia; Mojena, Marina; Rosales-Mendoza, César Eduardo; Emami, Hamed; Swanson, Jeffrey; Morss, Alex; Fayad, Zahi A.; Rudd, James H.F.; Gelfand, Jeffrey A.; Paz-García, Marta; Martı́n-Sanz, Paloma; Tawakol, Ahmed

doi:10.2967/jnumed.115.167387

Cited by 17 publications

(11 citation statements)

References 38 publications

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“…GM-CSF serum level was increased to more than 25-fold the healthy control levels in our patients. These results are in line with a previously reported Egyptian study that showed significant elevation in GM-CSF among chronic HCV patients [ 53 ]. Moreover, the increases in GM-CSF were correlated with increased lactate accumulation [ 54 ].…”

Section: Discussionsupporting

confidence: 93%

Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients

et al. 2021

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Introduction: Hepatitis C virus (HCV) is the main cause of chronic liver disease, with calamitous complications. Its highest rate is recorded in Egypt. This study investigated whether oxidative stress, immunological chaos and cellular hypoxia are implicated in the pathophysiology of the disease. Material and methods: This cross-sectional study aimed to evaluate the changes in blood oxidative stress, cellular hypoxia/angiogenesis and cellular immunological biomarkers in hospital-diagnosed treatment-naïve HCV-infected Upper Egyptian chronic liver disease patients vs. healthy controls (n = 40). The consecutively included patients comprised 120 with normal serum enzymes (HCV-NE) and 130 with high serum enzymes (HCV-HE), along with 120 cirrhotic patients. Results: Oxidative stress biomarkers-malondialdehyde (MDA), total peroxides and oxidative stress index (OSI)-were significantly lower in controls vs. each of the patient groups. Cirrhotic patients presented the highest levels. However, total antioxidants (TAO) showed non-significant differences among the four groups. The cellular hypoxia/angiogenesis biomarkers-lactate, vascular endothelial cell growth factor (VEGF) and its soluble receptor 1 (sVEG-FR1)-vs. controls were massively increased in patient groups. VEGF was lowest while sVEGFR1 was highest among cirrhotic patients. Immunological biomarkers,-granulocyte/monocyte-colony stimulating factor (GM-CSF) and total immunoglobulin G (IgG)-were massively increased in patient groups vs. controls. GM-CSF was lowest in HCV-HE and IgG was highest in cirrhotic patients. sVEGFR1 correlated with the progression towards cirrhosis. Conclusions: Oxidative stress is implicated in the progress of HCV infection with marked induction of cellular hypoxia and dysfunctional angiogenesis, and a futile immunological reaction. sVEGFR1 level correlated with progression towards HCV-induced liver fibrosis.

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Section: Discussionsupporting

confidence: 93%

Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients

et al. 2021

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“…Conversely, glycolytic inhibition of macrophages using siRNA against PFKFB3 or using 3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one, a selective inhibitor of PFKFB3, leads to a blockade in macrophage activation ( Tawakol et al, 2015 ). In vivo , this translated into decreased 18 F-fluorodexyglucose ( 18 F-FDG) uptake in the arterial vessel wall in Apoe –/– mice measured with positron emission tomography/computed tomography ( Singh et al, 2016 ), underscoring attenuated arterial wall inflammation following attenuation of inducible glycolysis in macrophages ( Tarkin et al, 2014 ). In our Ldlr knockout mice, we show that the progression of atherosclerosis is attenuated upon PFKFB3 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PFKFB3 Hampers the Progression of Atherosclerosis and Promotes Plaque Stability

Poels

Schnitzler

Waissi

et al. 2020

Front. Cell Dev. Biol.

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Aims 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3-mediated glycolysis is pivotal in driving macrophage- and endothelial cell activation and thereby inflammation. Once activated, these cells play a crucial role in the progression of atherosclerosis. Here, we analyzed the expression of PFKFB3 in human atherosclerotic lesions and investigated the therapeutic potential of pharmacological inhibition of PFKFB3 in experimental atherosclerosis by using the glycolytic inhibitor PFK158. Methods and Results PFKFB3 expression was higher in vulnerable human atheromatous carotid plaques when compared to stable fibrous plaques and predominantly expressed in plaque macrophages and endothelial cells. Analysis of advanced plaques of human coronary arteries revealed a positive correlation of PFKFB3 expression with necrotic core area. To further investigate the role of PFKFB3 in atherosclerotic disease progression, we treated 6–8 weeks old male Ldlr –/– mice. These mice were fed a high cholesterol diet for 13 weeks, of which they were treated for 5 weeks with the glycolytic inhibitor PFK158 to block PFKFB3 activity. The incidence of fibrous cap atheroma (advanced plaques) was reduced in PFK158-treated mice. Plaque phenotype altered markedly as both necrotic core area and intraplaque apoptosis decreased. This coincided with thickening of the fibrous cap and increased plaque stability after PFK158 treatment. Concomitantly, we observed a decrease in glycolysis in peripheral blood mononuclear cells compared to the untreated group, which alludes that changes in the intracellular metabolism of monocyte and macrophages is advantageous for plaque stabilization. Conclusion High PFKFB3 expression is associated with vulnerable atheromatous human carotid and coronary plaques. In mice, high PFKFB3 expression is also associated with a vulnerable plaque phenotype, whereas inhibition of PFKFB3 activity leads to plaque stabilization. This data implies that inhibition of inducible glycolysis may reduce inflammation, which has the ability to subsequently attenuate atherogenesis.

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“…For example, glucose analog 2-(18F)-fluoro-2-deoxy-D-glucose (FDG) concentrates in tissue with high glycolytic activity (79), including organs rich in inflammatory macrophages (80); this is readily detected by positron emission tomography. Granulocyte-macrophage colony-stimulating factor (GM-CSF), which attracts phagocytes to the heart (81), enhances macrophage glycolytic activity and 18F-FDG-update during inflammation in vivo (82), and after MI (83). More recent approaches have non-invasively imaged glycolytic cardiac inflammation with hyperpolarized magnetic resonance through employ of [1- 13 C] pyruvate and lactate (84).…”

Section: Macrophage Metabolism and Links To Cardiac Repairmentioning

confidence: 99%

Immunometabolism of Phagocytes and Relationships to Cardiac Repair

Zhang

Bories

Lantz

et al. 2019

Front. Cardiovasc. Med.

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Cardiovascular disease remains the leading cause of death worldwide. Myocardial ischemia is a major contributor to cardiovascular morbidity and mortality. In the case of acute myocardial infarction, subsequent cardiac repair relies upon the acute, and coordinated response to injury by innate myeloid phagocytes. This includes neutrophils, monocytes, macrophage subsets, and immature dendritic cells. Phagocytes function to remove necrotic cardiomyocytes, apoptotic inflammatory cells, and to remodel extracellular matrix. These innate immune cells also secrete cytokines and growth factors that promote tissue replacement through fibrosis and angiogenesis. Within the injured myocardium, macrophages polarize from pro-inflammatory to inflammation-resolving phenotypes. At the core of this functional plasticity is cellular metabolism, which has gained an appreciation for its integration with phagocyte function and remodeling of the transcriptional and epigenetic landscape. Immunometabolic rewiring is particularly relevant after ischemia and clinical reperfusion given the rapidly changing oxygen and metabolic milieu. Hypoxia reduces mitochondrial oxidative phosphorylation and leads to increased reliance on glycolysis, which can support biosynthesis of pro-inflammatory cytokines. Reoxygenation is permissive for shifts back to mitochondrial metabolism and fatty acid oxidation and this is ultimately linked to pro-reparative macrophage polarization. Improved understanding of mechanisms that regulate metabolic adaptations holds the potential to identify new metabolite targets and strategies to reduce cardiac damage through nutrient signaling.

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GM-CSF Enhances Macrophage Glycolytic Activity In Vitro and Improves Detection of Inflammation In Vivo

Cited by 17 publications

References 38 publications

Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients

Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients

Inhibition of PFKFB3 Hampers the Progression of Atherosclerosis and Promotes Plaque Stability

Immunometabolism of Phagocytes and Relationships to Cardiac Repair

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