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

Giulio Cavalli, JN Justice, KE Boyle, Angelo D'Alessandro, EZ Eisenmesser, JJ Herrera, KC Hansen, T Nemkov, R Stienstra, C Garlanda, A Mantovani, DR Seals, L Dagna, LAB Joosten, DB Ballak, CA Dinarello

Research output: Contribution to journalArticlepeer-review

Abstract

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. © 2017, National Academy of Sciences. All rights reserved.
Original languageEnglish
Pages (from-to)2313-2318
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number9
DOIs
Publication statusPublished - 2017

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