Credit: Carol and Mike Werner/Alamy Stock Photo

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.”