The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity
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
Affiliations
Giulio Cavalli
Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA; Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
Isak W. Tengesdal
Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
Mark Gresnigt
Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA; Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany
Travis Nemkov
Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA
Rob J.W. Arts
Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
Jorge Domínguez-Andrés
Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
Raffaella Molteni
Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy
Davide Stefanoni
Vita-Salute San Raffaele University, Milan, Italy
Eleonora Cantoni
Vita-Salute San Raffaele University, Milan, Italy
Laura Cassina
Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy
Silvia Giugliano
Laboratory of Mucosal Immunology and Microbiota, Humanitas Clinical and Research Center – IRCCS, via Manzoni 56, 20089 Rozzano (MI), Italy
Kiki Schraa
Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
Taylor S. Mills
Division of Hematology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
Eric M. Pietras
Division of Hematology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
Elan Z. Eisenmensser
Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA
Lorenzo Dagna
Vita-Salute San Raffaele University, Milan, Italy; Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Milan, Italy
Alessandra Boletta
Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy
Angelo D’Alessandro
Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA
Leo A.B. Joosten
Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
Mihai G. Netea
Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
Charles A. Dinarello
Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA; Corresponding author
Summary: 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.
