Objectives Accelerated atherosclerotic disease typically complicates rheumatoid arthritis (RA), leading to premature cardiovascular death. Inflammatory macrophages are key effector cells in both rheumatoid synovitis and the plaques of coronary artery disease (CAD). Whether both diseases share macrophage-dependent pathogenic mechanisms is unknown.
Methods Patients with RA or CAD (at least one myocardial infarction) and healthy age-matched controls were recruited into the study. Peripheral blood CD14+ monocytes were differentiated into macrophages. Metabolic profiles were assessed by Seahorse Analyzer, intracellular ATP concentrations were quantified and mitochondrial protein localisation was determined by confocal image analysis.
Results In macrophages from patients with RA or CAD, mitochondria consumed more oxygen, generated more ATP and built tight interorganelle connections with the endoplasmic reticulum, forming mitochondria-associated membranes (MAM). Calcium transfer through MAM sites sustained mitochondrial hyperactivity and was dependent on inactivation of glycogen synthase kinase 3b (GSK3b), a serine/threonine kinase functioning as a metabolic switch. In patient-derived macrophages, inactivated pGSK3b-Ser9 co-precipitated with the mitochondrial fraction. Immunostaining of atherosclerotic plaques and synovial lesions confirmed that most macrophages had inactivated GSK3b. MAM formation and GSK3b inactivation sustained production of the collagenase cathepsin K, a macrophage effector function closely correlated with clinical disease activity in RA and CAD.
Conclusions Re-organisation of the macrophage metabolism in patients with RA and CAD drives unopposed oxygen consumption and ultimately, excessive production of tissue-destructive enzymes. The underlying molecular defect relates to the deactivation of GSK3b, which controls mitochondrial fuel influx and as such represents a potential therapeutic target for anti-inflammatory therapy.
- rheumatoid arthritis
- cardiovascular disease
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Handling editor Josef S Smolen
Contributors MZ planned and performed experiments, was responsible for data analysis. HZ contributed expertise in tissue analysis. REY, RW, YL and LB contributed technical expertise. BBW and JH enrolled patients and JCG and TLA oversaw patient recruitment. CMW and JJG conceived the study, designed experiments and analysed data and CMW, JJG and MZ wrote the manuscript.
Funding This work was supported by the National Institutes of Health (R01 AR042527, R01 HL117913, R01 AI108906 and R01 AI108891, R01 AG045779, I01 BX001669), the Praespero Foundation and the Cahill Discovery Fund. MZ was funded by the German Research Foundation (DFG; ZE 1078/1-1).
Competing interests None declared.
Patient consent Obtained.
Ethics approval The study was approved by the Institutional Review Board at Stanford University.
Provenance and peer review Not commissioned; externally peer reviewed.
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