Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Highlights • 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.