New research by Giulio Cavalli and colleagues shows that the IL-1 family cytokine IL-37 not only has anti-inflammatory effects, but also induces metabolic reprogramming both in the context of inflammation-induced fatigue and in healthy mice. “We demonstrate a remarkable property of IL-37 to limit the metabolic costs of inflammation and to foster exercise tolerance,” explains co-author Charles Dinarello.
In mice with systemic inflammation induced by administration of low-dose lipopolysaccharide (LPS) (an established model of inflammation-induced fatigue associated with reduced exercise tolerance), treatment with recombinant human IL-37 reduced levels of inflammatory markers in muscle and serum and restored endurance running time to near baseline levels. “Given the known suppression of systemic inflammation by IL-37, it was not unexpected that exercise tolerance would improve upon IL-37 treatment,” remarks Dinarello. “However, the beneficial effects of IL-37 on exercise tolerance were more marked than those of anakinra, the anti-inflammatory IL-1 receptor antagonist, thus implying additional mechanisms of action beyond suppression of inflammation,” he continues.
Surpringly, IL-37 treatment also markedly improved exercise tolerance in healthy mice not subjected to LPS-induced inflammation. Endurance running time improved within 24 h of IL-37 administration, and by day 2 was 82% higher in IL-37-treated mice compared with vehicle-treated mice (P = 0.01); after eight daily doses of IL-37, the increase was 326% (P = 0.001). Cavalli et al. also showed that the effects of IL-37 on exercise tolerance are mediated by the IL-1 decoy receptor IL-1R8 (also known as TIR8, or single immunoglobulin IL-1R related receptor) and AMP-activated protein kinase (AMPK), as they were abrogated by AMPK inhibition or IL-1R8 deficiency.
treatment with IL-37 increased the flux of oxidative phosphorylation substrates and levels of AMPK in skeletal muscle
“These effects of IL-37 on exercise tolerance in healthy mice were not secondary to suppression of the inflammatory response,” says Dinarello. “Rather, we observed direct and profound effects on energy metabolism.” Specifically, treatment with IL-37 increased the flux of oxidative phosphorylation substrates and levels of AMPK in skeletal muscle. “Metabolomics analyses also revealed reduced levels of the proinflammatory mediator succinate and oxidative stress-related metabolites, and changes in amino acid and purine metabolism in muscles of treated animals,” adds Dinarello.
Fatigue is a debilitating but often neglected manifestation of chronic inflammatory diseases. “Our study provides the rationale for development of recombinant IL-37 in the treatment of inflammation-induced fatigue,” concludes Dinarello. “The ultimate goal is to have recombinant forms of IL-37 available to physicians to treat humans.”
References
Cavalli, G. et al. Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance. Proc. Natl Acad. Sci. USA http://dx.doi.org/10.1073/pnas.1619011114 (2017)
Rights and permissions
About this article
Cite this article
Onuora, S. IL-37 fights inflammation-induced fatigue. Nat Rev Rheumatol 13, 258 (2017). https://doi.org/10.1038/nrrheum.2017.28
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrrheum.2017.28