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OP0092 Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration and improves exercise tolerance
  1. G Cavalli1,
  2. D Ballak2,
  3. JJ Justice2,
  4. K Boyle3,
  5. A D'Alessandro3,
  6. LA Joosten4,
  7. L Dagna1,
  8. CA Dinarello5
  1. 1Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UniRAR), Vita-Salute San Raffaele University, Milan, Italy
  2. 2University of Colorado Boulder, Boulder, CO
  3. 3University of Colorado Denver, Aurora, CO, United States
  4. 4Radboud University Medical Center, Nijmegen, Netherlands
  5. 5Medicine, University of Colorado Denver, Aurora, CO, United States

Abstract

Background The IL-1 family cytokine interleukin 37 (IL-37) has broad anti-inflammatory effects and functions as a natural suppressor of innate inflammation and acquired immunity (1). We have reported that administration of recombinant human IL-37 to wild type mice or expression in mice transgenic for human IL-37 suppress proinflammatory cytokines and curb excessive inflammation in various conditions including inflammatory arthritis (2). Besides these anti-inflammatory effects, IL-37 also induces complex effects on metabolism. In particular, IL-37 can directly activate AMP-activated protein kinase (AMPK), a central regulator of cellular energy homeostasis and exercise-regulated metabolism (3).

Objectives In this study, we evaluate the effects of IL-37 treatment on exercise tolerance in mice with systemic inflammation induced by LPS injection. We further investigate the effects of IL-37 on exercise tolerance in healthy mice, with specific focus on the metabolic changes induced by IL-37 administration and possibly responsible for a reduction in the metabolic costs of inflammation.

Results Exogenous administration of IL-37 to healthy mice, not subjected to an inflammatory challenge, also improved exercise performance by 82% compared to vehicle-treated mice (p=0.01). Treatment with 8 daily doses of IL-37 resulted in a further 326% increase in endurance running time compared to 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), since 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 pro-inflammatory mediator succinate and oxidative stress-related metabolites as well as changes in amino acid and purine metabolism.

Conclusions 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.

References

  1. Dinarello CA, et al. (2016) Suppression of innate inflammation and immunity by interleukin-37. Eur J Immunol.

  2. Cavalli G, et al. (2016) Treating experimental arthritis with the innate immune inhibitor interleukin-37 reduces joint and systemic inflammation. Rheumatology (Oxford).

  3. Ballak DB, et al. (2014) IL-37 protects against obesity-induced inflammation and insulin resistance. Nature communications.

References

Disclosure of Interest None declared

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