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

Cell reports

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

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.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 33826894

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