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

Faas, Maria, Ipseiz, Natacha, Ackermann, Jochen, Culemann, Stephan, Grüneboom, Anika, Schröder, Fenja, Rothe, Tobias, Scholtysek, Carina, Eberhardt, Martin, Böttcher, Martin, Kirchner, Philipp, Stoll, Cornelia, Ekici, Arif, Fuchs, Maximilian, Kunz, Meik, Weigmann, Benno, Wirtz, Stefan, Lang, Roland, Hofmann, Joerg, Vera, Julio, Voehringer, David, Michelucci, Alessandro, Mougiakakos, Dimitrios, Uderhardt, Stefan, Schett, Georg and Krönke, Gerhard 2021. IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation. Immunity 54 (11) , pp. 2531-2546. 10.1016/j.immuni.2021.09.010

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Elsevier
ISSN: 1074-7613
Date of First Compliant Deposit: 26 January 2022
Date of Acceptance: 15 September 2021
Last Modified: 19 Sep 2022 01:59

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