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

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. [Display omitted] • IL-37 counteracts the protective effects of trained immunity (TI) in vivo • IL-37 suppresses pro-inflammatory cytokine production • IL-37 reverses immunometabolic changes and histone modifications characteristic of TI Cavalli et al. demonstrate that the anti-inflammatory cytokine IL-37 regulates trained immunity (TI) in vivo. IL-37 reverses the immunometabolic changes and histone post-translational modifications underlying TI, thereby suppressing pro-inflammatory cytokine production. This regulatory role of IL-37 over myeloid-driven inflammation has implications for immune-mediated disorders and for host responses against pathogens. [ABSTRACT FROM AUTHOR]