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

G Cavalli, JN Justice, KE Boyle… - Proceedings of the …, 2017 - National Acad Sciences
G Cavalli, JN Justice, KE Boyle, A D'Alessandro, EZ Eisenmesser, JJ Herrera, KC Hansen
Proceedings of the National Academy of Sciences, 2017National Acad Sciences
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 …
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.
National Acad Sciences