Abstract
TNF is a central cytokine in the pathogenesis of rheumatoid arthritis (RA). Elevated level of TNF causes local inflammation that affects immune cells and fibroblast-like synoviocytes (FLS). Nowadays, only 20–30% of patients experience remission after the standard of care therapy—antibodies against TNF. Interestingly, responders show reduced levels of GLUT1 and GAPDH, highlighting a potential link to cellular metabolism. The aim of the study was to investigate whether TNF directly affects the metabolic phenotype of FLS. Real-time respirometry displayed TNF-induced upregulation of glycolysis along with a modest increase of oxidative phosphorylation in FLS from healthy donors. In addition, TNF stimulation enhanced HIF1A and GLUT1 expression. The upregulation of HIF1A and GLUT1 reflects their enriched level in FLS from RA patients (RA-FLS). The inhibition of TAK1, HIF1a and hexokinase deciphered the importance of TNF/TAK1/HIF1A/glycolysis signaling axis. To prove that inhibition of glycolysis reduced the pathogenic phenotype, we showed that 2-deoxyglucose, a hexokinase inhibitor, partially decreased secretion of RA biomarkers. In summary, we identified a direct role of TNF on glycolytic reprogramming of FLS and confirmed the potency of immunometabolism for RA. Further studies are needed to evaluate the therapeutic impact especially regarding non-responder data.
Highlights
TNF is a central cytokine in the pathogenesis of rheumatoid arthritis (RA)
Abbreviations 2-DG 2-Deoxyglucose FDG-PET Fluordesoxyglucose positron emission tomography fibroblast-like synoviocytes (FLS) Fibroblast-like synoviocytes GAPDH Glyceraldehyde 3-phosphate dehydrogenase GLUT1 Glucose transporter 1 H-FLS Fibroblast-like synoviocytes from healthy donor HIF1A Hypoxia-Inducible Factor-1 hexokinase 2 (HK2) Hexokinase 2 ICAM1 Intercellular Adhesion Molecule 1 mitogen-activated protein kinases (MAPK) Mitogen-activated protein kinase matrix metalloproteases (MMP) Matrix metalloprotease nuclear factorkappa-light-chain-enhancerof activated B-cells (NF-kB) Nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells OA Osteoarthritis pyruvate dehydrogenase kinase 4 (PDK4) Pyruvate dehydrogenase kinase 4 PFKFB3 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 PFKL Phosphofructokinase PGK1 Phosphoglycerate kinase PK Pyruvate kinase peroxisome proliferator-activated receptor gamma (PPARG) Peroxisome proliferator-activated receptor gamma RA Rheumatoid arthritis RA-FLS Fibroblast-like synoviocytes from RA donor receptor-interacting protein (RIP) Receptor-interacting protein TAK1 TGF-Beta Activated Kinase 1 TNF Tumor Necrosis Factor alpha
To find out whether stimulation with TNF directly promotes metabolic changes in FLS, Seahorse glycolysis stress test was performed in FLS from healthy donors (H-FLS) upon treatment with TNF
Summary
Elevated level of TNF causes local inflammation that affects immune cells and fibroblast-like synoviocytes (FLS). Abbreviations 2-DG 2-Deoxyglucose FDG-PET Fluordesoxyglucose positron emission tomography FLS Fibroblast-like synoviocytes GAPDH Glyceraldehyde 3-phosphate dehydrogenase GLUT1 Glucose transporter 1 H-FLS Fibroblast-like synoviocytes from healthy donor HIF1A Hypoxia-Inducible Factor-1 HK2 Hexokinase 2 ICAM1 Intercellular Adhesion Molecule 1 MAPK Mitogen-activated protein kinase MMP Matrix metalloprotease NF-kB Nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells OA Osteoarthritis PDK4 Pyruvate dehydrogenase kinase 4 PFKFB3 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 PFKL Phosphofructokinase PGK1 Phosphoglycerate kinase PK Pyruvate kinase PPARG Peroxisome proliferator-activated receptor gamma RA Rheumatoid arthritis RA-FLS Fibroblast-like synoviocytes from RA donor RIP Receptor-interacting protein TAK1 TGF-Beta Activated Kinase 1 TNF Tumor Necrosis Factor alpha. The current standard of care therapy do not cure the disease and only 20–30% of patients experience remission[11]. We questioned whether a single cytokine like TNF is able to induce metabolic reprogramming and proinflammatory phenotype in FLS from healthy donors (H-FLS) to the described phenotype of RA-FLS
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