The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity
Giulio Cavalli, Isak W. Tengesdal, Mark S. Gresnigt, Travis Nemkov, Rob J.W. Arts, Jorge Domínguez‐Andrés, Raffaella Molteni, Davide Stefanoni, Eleonora Cantoni, Laura Cassina, Silvia Giugliano, Kiki Schraa, Taylor Mills, Eric M. Pietras, Elan Z. Eisenmensser, Lorenzo Dagna, Alessandra Boletta, Angelo D’Alessandro, Leo A. B. Joosten, Mihai G. Netea, Charles A. Dinarello
Abstract
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.