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

Maria Faas, Natacha Ipseiz, Jochen Ackermann, Stephan Culemann, Anika Grüneboom, Fenja Schröder, Tobias Rothe, Carina Scholtysek, Martin Eberhardt, Martin Böttcher, Philipp Kirchner, Cornelia Stoll, Arif Ekici, Maximilian Fuchs, Meik Kunz, Benno Weigmann, Stefan Wirtz, Roland Lang, Joerg Hofmann, Julio VeraDavid Voehringer, Alessandro Michelucci, Dimitrios Mougiakakos, Stefan Uderhardt, Georg Schett, Gerhard Krönke*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2531-2546.e5
JournalImmunity
Volume54
Issue number11
DOIs
Publication statusPublished - 9 Nov 2021

Keywords

  • alternatively activated macrophage
  • GATA3
  • interleukin-33
  • itaconate
  • mitochondrial rewiring
  • resolution of inlammation
  • UCP2
  • uncoupling

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