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

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 11; pp. 2531 - 2546.e5
• Main Authors: 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, Krönke, Gerhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.11.2021
• Subjects: alternatively activated macrophage; Biomarkers; Cell Differentiation - genetics; Cell Differentiation - immunology; Energy Metabolism; GATA3; Inflammation - etiology; Inflammation - immunology; Inflammation - metabolism; interleukin-33; Interleukin-33 - metabolism; itaconate; Macrophage Activation - genetics; Macrophage Activation - immunology; Macrophages - immunology; Macrophages - metabolism; Mitochondria - genetics; Mitochondria - immunology; Mitochondria - metabolism; mitochondrial rewiring; Phagocytes; resolution of inlammation; Signal Transduction; UCP2; uncoupling; uncoupling; itaconate; mitochondrial rewiring; resolution of inlammation; alternatively activated macrophage; UCP2; GATA3; interleukin-33
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.09.010

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. [Display omitted] •IL-33 induces rapid mitochondrial rewiring in macrophages•Uncoupling of the respiratory chain promotes IL-33-induced AAM differentiation•GATA3 links macrophage metabolism and differentiation in response to IL-33•GATA3 orchestrates the differentiation of pro-resolving macrophages in vivo Alternatively activated macrophages (AAMs) promote the resolution of inflammation and tissue repair. Faas et al. show that the alarmin IL-33 promotes a mitochondrial rewiring of macrophages and the consecutive activation of the transcription factor GATA3, which orchestrates the IL-4-independent differentiation of AAMs and the resolution of inflammation upon tissue injury.