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

Cavalli, Giulio; Tengesdal, Isak W; Gresnigt, Mark; Nemkov, Travis; Arts, Rob J W; Domínguez-Andrés, Jorge; Molteni, Raffaella; Stefanoni, Davide; Cantoni, Eleonora; Cassina, Laura; Giugliano, Silvia; Schraa, Kiki; Mills, Taylor S; Pietras, Eric M; Eisenmensser, Elan Z; Dagna, Lorenzo; Boletta, Alessandra; D'Alessandro, Angelo; Joosten, Leo A B; Netea, Mihai G; Dinarello, Charles A

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.