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Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance

Significance Interleukin 1 family member IL-37 is a naturally occurring inhibitor of inflammation. In this study, exogenous administration of recombinant human IL-37 reversed the decrease in exercise performance observed during systemic inflammation. IL-37 also increased exercise performance in healthy mice. IL-37 treatment acted through a dual mechanism of suppression of inflammation and modulation of metabolic pathways. The implications of the present findings impact on patients with chronic inflammatory diseases spanning from rheumatoid arthritis to cancer, in which fatigue is often incapacitating, and provide rationale for exploring recombinant IL-37 in the treatment of inflammation-mediated fatigue. IL-1 family member interleukin 37 (IL-37) has broad antiinflammatory properties and functions as a natural suppressor of innate inflammation. In this study, we demonstrate that treatment with recombinant human IL-37 reverses the decrease in exercise performance observed during systemic inflammation. This effect was associated with a decrease in the levels of plasma and muscle cytokines, comparable in extent to that obtained upon IL-1 receptor blockade. Exogenous administration of IL-37 to healthy mice, not subjected to an inflammatory challenge, also improved exercise performance by 82% compared with vehicle-treated mice (P = 0.01). Treatment with eight daily doses of IL-37 resulted in a further 326% increase in endurance running time compared with the performance level of mice receiving vehicle (P = 0.001). These properties required the engagement of the IL-1 decoy receptor 8 (IL-1R8) and the activation of AMP-activated protein kinase (AMPK), because both inhibition of AMPK and IL-1R8 deficiency abrogated the positive effects of IL-37 on exercise performance. Mechanistically, treatment with IL-37 induced marked metabolic changes with higher levels of muscle AMPK, greater rates of oxygen consumption, and increased oxidative phosphorylation. Metabolomic analyses of plasma and muscles of mice treated with IL-37 revealed an increase in AMP/ATP ratio, reduced levels of proinflammatory mediator succinate and oxidative stress-related metabolites, as well as changes in amino acid and purine metabolism. These effects of IL-37 to limit the metabolic costs of chronic inflammation and to foster exercise tolerance provide a rationale for therapeutic use of IL-37 in the treatment of inflammation-mediated fatigue.