Fructose 1,6-bisphosphate, a high-energy intermediate of glycolysis, attenuates experimental arthritis by activating anti-inflammatory adenosinergic pathway

Veras, Flávio P.; Peres, Raphael Sanches; Saraiva, André Lopes; Pinto, Lidiane de Castro; Louzada‐Júnior, Paulo; Cunha, Thiago M.; Paschoal, Jonas Augusto Rizzato; Cunha, Fernando Q.; Alves-Filho, José C.

doi:10.1038/srep15171

Cited by 52 publications

(38 citation statements)

References 47 publications

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“…The counterintuitive scenario that sluggish instead of hyperactive glycolytic flux feeds inflammatory activity has been confirmed in animal models of arthritis [32]. Replenishing the product of PFKFB3, fructose 1,6-bisphosphate (FBP) provided strong anti-inflammatory effects in vivo, compatible with the concept that enhancing glycolytic breakdown improves T-cell function and prevents pro-inflammatory effector functions.…”

Section: Ra T-cells – Energy-deprived T-cells With Impaired Redox Sigmentioning

confidence: 89%

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Weyand

Zeisbrich

Goronzy

2017

Current Opinion in Immunology

116

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In most autoimmune diseases, a decade-long defect in self-tolerance eventually leads to clinically relevant, tissue-destructive inflammatory disease. The pathogenic potential of chronic persistent immune responses during the pre-clinical and clinical phase is ultimately linked to the bioenergetic fitness of innate and adaptive immune cells. Chronic immune cell stimulation, high cellular turn-over, structural damage to the host tissue and maladaptive wound healing, all require a reliable supply of nutrients, oxygen, and biosynthetic precursors. Here, we use the model system of rheumatoid arthritis (RA) to discuss immunometabolism from the vantage point of T-cells and macrophages that encounter fundamentally different metabolic stress scenarios in the RA host. We outline the general principle that both insufficient nutrient supply, as well as nutrient excess generate cellular stress responses and guide immune function. ATPlow, NADPHhigh, ROSlow T-cells hyperproliferate and are forced into premature senescence. ATPhigh, ROShigh macrophages dimerize the glycolytic enzyme pyruvate kinase to amplify STAT3-dependent inflammatory effector functions. A corollary of this model is that simple nutraceutical interventions will be insufficient to re-educate the immune system in RA. Instead, interference with cell-type-exclusive and differentiation-stage-dependent metabolic setpoints will be needed to reprogram arthritogenic pathways.

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Section: Ra T-cells – Energy-deprived T-cells With Impaired Redox Sigmentioning

confidence: 89%

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Weyand

Zeisbrich

Goronzy

2017

Current Opinion in Immunology

116

View full text Add to dashboard Cite

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“…Treatments with drugs increasing mitochondrial oxidation ( 9 ) or preventing FA synthesis ( 11 ) normalized the metabolism of these T cells, and decreased their infiltration into synovial tissue implanted in humanized mice. In the zymosan-induced model of arthritis, treatment with fructose 1,6-bisphosphate (FBP), the product of PFKFB3, attenuated disease severity ( 12 ). Lymphocytes infiltrating the joints of RA patients express a high levels of hexokinase HK2 , indicating that they are also highly glycolytic, which is consistent with their activation status ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis

et al. 2018

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The K/BxN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4+ T cells from the KRN strain that are activated by glucose-6-phosphate isomerase (GPI) peptides presented by the H-2g7 allele from the NOD strain. It is a model of autoimmune seropositive arthritis because the production of anti-GPI IgG is necessary and sufficient for joint pathology. The production of high levels of anti-GPI IgG requires on the expansion of CD4+ follicular helper T (Tfh) cells. The metabolic requirements of this expansion have never been characterized. Based on the therapeutic effects of the combination of metformin and 2-deoxyglucose (2DG) in lupus models that normalized the expansion of effector CD4+ T cells. We showed that the CD4+ T cells and to a lesser extent, the B cells from K/BxN mice are more metabolically active than the KRN controls. Accordingly, preventive inhibition of glycolysis with 2DG significantly reduced joint inflammation and the activation of both adaptive and innate immune cells, as well as the production of pathogenic autoantibodies. However, contrary to the lupus-prone mice, the addition of metformin had little beneficial effect, suggesting that glycolysis is the major driver of immune activation in this model. We propose that K/BxN mice are another model in which autoreactive Tfh cells are highly glycolytic and that their function can be limited by inhibiting glucose metabolism.

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“…We found that less macrophages infiltrated into the graft and the expression levels of TNF‐α appeared to be reduced in the FBP administration group. The anti‐inflammatory effect of FBP has been documented . The addition of FBP to the culture medium inhibited the release of TNF‐α and interleukin‐6 production in lipopolysaccharide‐exposed alveolar macrophages in the early phase of the inflammatory response , which suggest that FBP acts as a cytokine inhibitor and provides anti‐inflammatory effects.…”

Section: Discussionmentioning

confidence: 99%

Fructose 1,6-Bisphosphate as a Protective Agent for Experimental Fat Grafting

et al. 2019

Stem Cells Translational Medicine

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Fat grafting procedures are considered to be a promising regenerative, cell‐directed therapy; however, their survival is mainly influenced by ischemia condition. Fructose 1,6‐bisphosphate (FBP), as an intermediate in energy metabolism, has the potential to rescue cells and tissues from hypoxic‐ischemic circumstances. In the present study, human lipoaspirates were grafted subcutaneously into nude mice followed by a daily intraperitoneal injection of FBP at different doses for 7 days. Next, the grafts were harvested at different time points till 12 weeks postimplantation and were evaluated for cell viability and function, tissue revascularization and inflammatory cell infiltration using histological analysis, whole‐mount living tissue imaging, glycerol 3‐phosphate dehydrogenase activity assays, and quantitative analysis of gene expression. The results demonstrated that exogenous FBP administration could attenuate the volume and weight reduction of fat graft; meanwhile, FBP enhanced adipocyte viability and function, increased blood vessel formation, and decreased inflammation. Moreover, in vitro cell experiments showed that FBP could promote adipose‐derived stem cell viability and vascular endothelial growth factor (VEGF) mRNA expression in ischemia conditions. Our study indicates that FBP can be used as a protective agent for fat grafting and may be applied in stem cell‐based regenerative medicine. stem cells translational medicine 2019;8:606–616

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Fructose 1,6-bisphosphate, a high-energy intermediate of glycolysis, attenuates experimental arthritis by activating anti-inflammatory adenosinergic pathway

Cited by 52 publications

References 47 publications

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Inhibition of Glycolysis Reduces Disease Severity in an Autoimmune Model of Rheumatoid Arthritis

Fructose 1,6-Bisphosphate as a Protective Agent for Experimental Fat Grafting

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