biostudies-literatureFaas MBundesministerium für Bildung und ForschungDeutsche ForschungsgemeinschaftEuropean Research CouncilFriedrich-Alexander-Universität Erlangen-Nürnberg2531-2546.e5https://www.ebi.ac.uk/biostudies/studies/S-EPMC7617137biostudies-literatureUnknown54(11)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 ImmunityIL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation.PMC7617137261193037GK1660B01/A03640087FG 2886CRC1181-A03/A01/A02/Z2810316101001866Schroder FGruneboom AKirchner PCulemann SFaas MMougiakakos DKronke GRothe TIpseiz NStoll CSchett GWirtz SVoehringer DBottcher MKunz MEberhardt MUderhardt SVera JMichelucci AAckermann JEkici AFuchs MHofmann JLang RScholtysek CWeigmann BfalseIL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation.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 2021-01-01T00:00:00Z2021 Nov2026-06-03T01:09:23.209Z2025-04-03T23:18:48.067ZS-EPMC76171373464453710.1016/j.immuni.2021.09.010