Bioenergetics of immune cells to assess rheumatic disease activity and efficacy of glucocorticoid treatment

Kuhnke, A.; Gr, Burgio; Krauß, Stefan; Buttgereit, Frank

doi:10.1136/ard.62.2.133

Cited by 40 publications

(24 citation statements)

References 36 publications

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“…The specificity of Bz-423 for pathogenic lymphocytes, and its ability to preserve normal immune reconstitution, differentiates it from high dose systemic steroids, currently the standard treatment for GVHD (39, 40). This mechanism of action is also consistent with the therapeutic benefits of Bz-423 in models of autoimmune disease, where pathogenic cells have similar bioenergetic characteristics, increased respiration and depleted antioxidant reserves (8, 9). Recently, several groups have shown that mitochondrial metabolism can be pharmacologically manipulated during an immune response to promote the generation of memory cells and protective immunity (41, 42).…”

Section: Discussionsupporting

confidence: 80%

“…The bioenergetic imbalances of alloreactive T cells result in the accumulation of acylcarnitines, excess superoxide, increased ΔΨ m , and diminished antioxidant reserves. While the basis for these changes has yet to be fully elucidated, they may be related to metabolic adaptations that occur as a result of chronic activation in the context of disease (8, 9). Similar changes have also been identified in other immune disorders and thus may represent a general feature of pathogenic T cells (9).…”

Section: Discussionmentioning

confidence: 99%

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Manipulating the Bioenergetics of Alloreactive T Cells Causes Their Selective Apoptosis and Arrests Graft-Versus-Host Disease

et al. 2011

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Cells generate ATP by glycolysis and by oxidative phosphorylation (OXPHOS) (1, 2). Despite the importance of having sufficient ATP available for the energy-dependent processes involved in immune activation, little is known about the metabolic adaptations that occur in vivo to meet the increased demand for ATP in activated and proliferating lymphocytes. We found that bone marrow (BM) cells proliferating after bone marrow transplantation (BMT) increased aerobic glycolysis but not OXPHOS, while T cells proliferating in response to alloantigens during graft versus host disease (GVHD) increased both aerobic glycolysis and OXPHOS. Metabolomic analysis of alloreactive T cells showed an accumulation of acylcarnitines consistent with changes in fatty acid oxidation. Alloreactive T cells also exhibited a hyperpolarized mitochondrial membrane potential (ΔΨm), increased superoxide production and decreased antioxidant levels, whereas proliferating BM cells did not. Bz-423, a novel small molecule inhibitor of the mitochondrial F1F0-ATPase, selectively increased superoxide and induced the apoptosis of alloreactive T cells, which arrested established GVHD in several BMT models without affecting hematopoietic engraftment or lymphocyte reconstitution. These findings challenge the current paradigm that activated T cells meet their increased demands for ATP though aerobic glycolysis, and identify the possibility that bioenergetic and redox characteristics can be selectively exploited as a novel therapeutic strategy for immune disorders.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Manipulating the Bioenergetics of Alloreactive T Cells Causes Their Selective Apoptosis and Arrests Graft-Versus-Host Disease

et al. 2011

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“…Although the Clark electrode can be used to measure oxygen consumption rate in blood cells in suspension, the presented method uses fewer cells (6×10 5 vs. 10 7 ), reflecting the greater sensitivity of the Seahorse device. 20,21,28 Other approaches for measuring mitochondrial function in humans have included measurement of mitochondrial enzyme activity in biopsied tissue and by magnetic resonance spectroscopy. 29,30 Such studies are invasive or require expensive equipment, and are poorly suited to the larger scale epidemiological or intervention studies that would be required to understand how mitochondrial function relates to disease risk or management.…”

Section: Discussionmentioning

confidence: 99%

Relation of mitochondrial oxygen consumption in peripheral blood mononuclear cells to vascular function in type 2 diabetes mellitus

et al. 2014

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Recent studies have shown mitochondrial dysfunction and increased production of reactive oxygen species in peripheral blood mononuclear cells (PBMC’s) and endothelial cells from patients with diabetes mellitus. Mitochondria oxygen consumption is coupled to ATP production and also occurs in an uncoupled fashion during formation of reactive oxygen species by components of the electron transport chain and other enzymatic sites. We therefore hypothesized that diabetes would be associated with higher total and uncoupled oxygen consumption in PBMC’s that would correlate with endothelial dysfunction. We developed a method to measure oxygen consumption in freshly isolated PBMC’s and applied it to 26 patients with type 2 diabetes mellitus and 28 non-diabetic controls. Basal (192±47 vs. 161±44 pMoles/min, P=0.01), uncoupled (64±16 vs. 53±16 pMoles/min, P=0.007), and maximal (795±87 vs. 715±128 pMoles/min, P=0.01) oxygen consumption rates were higher in diabetic patients compared to controls. There were no significant correlations between oxygen consumption rates and endothelium-dependent flow-mediated dilation measured by vascular ultrasound. Non-endothelium-dependent nitroglycerin-mediated dilation was lower in diabetics (10.1±6.6 vs. 15.8±4.8%, P=0.03) and correlated with maximal oxygen consumption (R= −0.64, P=0.001). In summary, we found that diabetes mellitus is associated with a pattern of mitochondrial oxygen consumption consistent with higher production of reactive oxygen species. The correlation between oxygen consumption and nitroglycerin-mediated dilation may suggest a link between mitochondrial dysfunction and vascular smooth muscle cell dysfunction that merits further study. Finally, the described method may have utility for assessment of mitochondrial function in larger scale observational and interventional studies in humans.

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“…Indeed, an increased rate of O 2 consumption has been described in PMBC of patients with systemic lupus erythematosus (45) and active rheumatic diseases (46). Because high levels of ATP are required to sustain energy consuming by immune processes, it seems likely that interfering with lymphocyte's bioenergetic might help to reduce inflammatory reaction.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

Fiorucci

Mencarelli

Distrutti

et al. 2004

The Journal of Immunology

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The 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) is a NO-releasing derivative of aspirin. In this study, we provide evidence that NCX-4016 delivered to PMBC-derived T lymphocytes and monocytes causes a transitory inhibition of cell respiration and ≈50% reduction of cellular ATP, which translates in a time-reversible inhibition of cell proliferation and IL-2, IL-4, IL-5, and IFN-γ secretion. Exposure of lymphocytes and monocytes to aspirin, 2-(acetyloxy)benzoic acid 3-(hydroxymethyl)phenyl ester (NCX-4017), a non-NO-releasing analog of NCX-4016, and cyclooxygenase inhibitors, reduced PG formation, but has no effect on cytokine/chemokine release. In contrast, delivering NO with (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate (DETA-NO) reproduced most of the metabolic and anti-cytokine activities of NCX-4016. Scavenging NO with hemoglobin or adding selective substrates of complex II, III, and IV of the mitochondrial respiratory chain reverses NCX-4016′ inhibitory activities. Exposure to DETA-NO and NCX-4016 enhances glucose uptake, glycolytic rate, and lactate generation in CD3/CD28-costimulated lymphocytes, while reduced citric acid cycle intermediates. These effects were not reproduced by selective and nonselective cyclooxygenase 2 inhibitors. In summary, we demonstrated that exposure of lymphocytes to NCX-4016 causes a metabolic hypoxia that inhibits lymphocyte reactivity to costimulatory molecules, providing a potential counteregulatory mechanism to control activated immune system.

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Bioenergetics of immune cells to assess rheumatic disease activity and efficacy of glucocorticoid treatment

Cited by 40 publications

References 36 publications

Manipulating the Bioenergetics of Alloreactive T Cells Causes Their Selective Apoptosis and Arrests Graft-Versus-Host Disease

Manipulating the Bioenergetics of Alloreactive T Cells Causes Their Selective Apoptosis and Arrests Graft-Versus-Host Disease

Relation of mitochondrial oxygen consumption in peripheral blood mononuclear cells to vascular function in type 2 diabetes mellitus

Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

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