Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

- In the autoimmune disease, rheumatoid arthritis (RA), abnormal metabolic programs have been identified in arthritogenic T-cells and in macrophages.
- RA T-cells divert glucose from energy generation towards synthesis of biomass precursors and are ATPlow, NADPHhigh, and ROSlow. Functional consequences include hyperproliferation, G2/M bypass and deviated functional commitment.
- Energy-deprived, hyperproliferative RA T-cells lose activity of the DNA repair nuclease MRE11A, accumulate telomeric damage and enter premature senescence.
- RA macrophages overindulge on glucose and are ATPhigh and ROShigh. Oxidative modification of pyruvate kinase enables this cytoplasmic enzyme to enter the nucleus, phosphorylate STAT3 and promote IL-6 production.
- The coexistence of energy-deprived T-cells and glucose-overconsuming macrophages thwarts simple metabolic interferences (e.g., glucose restriction or oversupply), and necessitates cell type- and microenvironment-specific metabolic interventions.

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.