IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation

  • Immunity. 2021 Nov 9;54(11):2531-2546.e5. doi: 10.1016/j.immuni.2021.09.010.
Maria Faas  1 ,  Natacha Ipseiz  2 ,  Jochen Ackermann  1 ,  Stephan Culemann  1 ,  Anika Grüneboom  3 ,  Fenja Schröder  1 ,  Tobias Rothe  1 ,  Carina Scholtysek  1 ,  Martin Eberhardt  4 ,  Martin Böttcher  5 ,  Philipp Kirchner  6 ,  Cornelia Stoll  1 ,  Arif Ekici  6 ,  Maximilian Fuchs  7 ,  Meik Kunz  7 ,  Benno Weigmann  8 ,  Stefan Wirtz  8 ,  Roland Lang  9 ,  Joerg Hofmann  10 ,  Julio Vera  4 ,  David Voehringer  11 ,  Alessandro Michelucci  12 ,  Dimitrios Mougiakakos  5 ,  Stefan Uderhardt  1 ,  Georg Schett  1 ,  Gerhard Krönke  13
Affiliations
  • 1. Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany.
  • 2. Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany; Systems Immunity Research Institute, Heath Park, Cardiff University, Cardiff CF14 4XN, UK.
  • 3. Department of Biopsectroscopy, Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund 44139, Germany; Medical Faculty, University Hospital, University Duisburg-Essen, Essen 45147, Germany.
  • 4. Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany; Laboratory of Systems Tumor Immunology, Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
  • 5. Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany; Department of Internal Medicine 5, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany.
  • 6. Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany.
  • 7. Department of Medical Informatics, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany.
  • 8. Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany; Department of Internal Medicine 1, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany.
  • 9. Institute of Clinical Microbiology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany.
  • 10. Division of Biochemistry, Department of Biology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany.
  • 11. Division of Infection Biology, Institute of Clinical Microbiology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany.
  • 12. Neuro-Immunology Group, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg 1526, Luxembourg.
  • 13. Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen 91054, Germany. Electronic address: [email protected].
PMID: 34644537 DOI: 10.1016/j.immuni.2021.09.010
Abstract

Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.

Keywords
GATA3; UCP2; alternatively activated macrophage; interleukin-33; itaconate; mitochondrial rewiring; resolution of inlammation; uncoupling.