Journal
IMMUNITY
Volume 54, Issue 11, Pages 2531-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2021.09.010
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [CRC1181-A03/A01/A02/Z2, GK1660, FG 2886]
- Emerging Field Initiative (EFI) of Friedrich-Alexander University Erlangen-NuEurornberg (FAU) [EFI_Verbund_Med_05_MIRACLE]
- Bundesministerium fuEuror Bildung und Forschung (BMBF) [FKZ:01ZX1905A]
- DFG (German Research Foundation) [261193037]
- European Union (Horizon 2020 ERC-2014-StG) [640087]
- European Union (Horizon 2020 ERC-2020-CoG) [101001866]
- European Union (Horizon 2020 ERC-2018-SyG nano-SCOPE and RTCure)
- European Research Council (ERC) [101001866, 640087] Funding Source: European Research Council (ERC)
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Uncoupling protein-2 and the transcription factor GATA3 were found to regulate the differentiation of AAMs in response to IL-33, leading to their polarization. IL-33 induced metabolic rewiring in macrophages, which subsequently triggered GATA3-mediated AAM polarization.
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.
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