The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity

Cell Rep. 2021 Apr 6;35(1):108955. doi: 10.1016/j.celrep.2021.108955.


Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.

Keywords: IL-1 family; cell energy metabolism; cytokines; epigenetics; immunometabolism; infection; inflammation; innate immunity; neutrophils; regulatory cytokine; trained immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Candidiasis / genetics
  • Candidiasis / immunology
  • Candidiasis / microbiology
  • Epigenesis, Genetic / drug effects
  • Glycolysis / drug effects
  • Glycolysis / genetics
  • Host-Pathogen Interactions / drug effects
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity, Innate* / drug effects
  • Interleukin-1 / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / drug effects
  • Neutrophils / metabolism


  • Anti-Inflammatory Agents
  • IL37 protein, human
  • Interleukin-1