Abstract
Cancer cells have long been known to fuel their pathogenic growth habits by sustaining a high glycolytic flux, first described almost 90 years ago as the so-called Warburg effect. Immune cells utilize a similar strategy to generate the energy carriers and metabolic intermediates they need to produce biomass and inflammatory mediators. Resting lymphocytes generate energy through oxidative phosphorylation and breakdown of fatty acids, and upon activation rapidly switch to aerobic glycolysis and low tricarboxylic acid flux. T cells in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have a disease-specific metabolic signature that may explain, at least in part, why they are dysfunctional. RA T cells are characterized by low adenosine triphosphate and lactate levels and increased availability of the cellular reductant NADPH. This anti-Warburg effect results from insufficient activity of the glycolytic enzyme phosphofructokinase and differentiates the metabolic status in RA T cells from those in cancer cells. Excess production of reactive oxygen species and a defect in lipid metabolism characterizes metabolic conditions in SLE T cells. Owing to increased production of the glycosphingolipids lactosylceramide, globotriaosylceramide and monosialotetrahexosylganglioside, SLE T cells change membrane raft formation and fail to phosphorylate pERK, yet hyperproliferate. Borrowing from cancer metabolomics, the metabolic modifications occurring in autoimmune disease are probably heterogeneous and context dependent. Variations of glucose, amino acid and lipid metabolism in different disease states may provide opportunities to develop biomarkers and exploit metabolic pathways as therapeutic targets.
Highlights
More than 90 years ago, physician-scientist Otto Warburg proposed that cancer is, in principle, a metabolic disease characterized by a mitochondrial defect that shifts energy production towards glycolysis [1]
glucose transporter 1 (Glut1) is not expressed at significant levels on the surface of resting T cells, but is rapidly translocated to the plasma membrane through the Akt signaling pathway, which increases glycolysis by promoting the activities of the rate-limiting glycolytic enzymes hexokinase and phosphofructokinase
The analysis focused on naïve CD4 T cells, excluding T cells directly involved in the inflammatory process itself
Summary
More than 90 years ago, physician-scientist Otto Warburg proposed that cancer is, in principle, a metabolic disease characterized by a mitochondrial defect that shifts energy production towards glycolysis [1]. Able to metabolize fatty and amino acids in addition to glucose, and depend on oxidative phosphorylation (OXPHOS) to generate ATP [9] (Table 1). Nonactivated T cells and B cells predominantly oxidize glucose-derived pyruvate in the TCA cycle and access lipids and amino acids as needed.
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