[en] Macrophages undergo extensive metabolic reprogramming during classical pro-inflammatory polarization (M1-like). The accumulation of itaconate has been recognized as both a consequence and mediator of the inflammatory response. In this study we first examined the specific functions of itaconate inside fractionated mitochondria. We show that M1 macrophages produce itaconate de novo via aconitase decarboxylase 1 (ACOD1) inside mitochondria. The carbon for this reaction is not only supplied by oxidative TCA cycling, but also through the reductive carboxylation of α-ketoglutarate by isocitrate dehydrogenase (IDH). While macrophages are capable of sustaining a certain degree of itaconate production during hypoxia by augmenting the activity of IDH-dependent reductive carboxylation, we demonstrate that sufficient itaconate synthesis requires a balance of reductive and oxidative TCA cycle metabolism in mouse macrophages. In comparison, human macrophages increase itaconate accumulation under hypoxic conditions by augmenting reductive carboxylation activity. We further demonstrated that itaconate attenuates reductive carboxylation at IDH2, restricting its own production and the accumulation of the immunomodulatory metabolites citrate and 2-hydroxyglutarate. In line with this, reductive carboxylation is enhanced in ACOD1-depleted macrophages. Mechanistically, the inhibition of IDH2 by itaconate is linked to the alteration of the mitochondrial NADP+/NADPH ratio and competitive succinate dehydrogenase inhibition. Taken together, our findings extend the current model of TCA cycle reprogramming during pro-inflammatory macrophage activation and identified novel regulatory properties of itaconate.
Disciplines :
Immunology & infectious disease
Author, co-author :
Heinz, Alexander; Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
Nonnenmacher, Yannic; Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
Henne, Antonia; Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
Khalil, Michelle-Amirah; Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
Bejkollari, Ketlin; Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
Dostert, Catherine; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
Hosseini, Shirin; Department of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, Germany
Goldmann, Oliver; Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
He, Wei; Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
Palorini, Roberta; Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, Milan, Italy
Verschueren, Charlène; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
Korte, Martin; Department of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, Germany, Neuroinflammation and Neurodegeneration Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
Chiaradonna, Ferdinando; Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, Milan, Italy
Medina, Eva; Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics
Hiller, Karsten; Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany. Electronic address: karsten.hiller@tu-braunschweig.de
This work was funded by the Federal State of Lower Saxony, Niedersächsisches Vorab ( VWZN3266 ), (KH), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project HI1400/3-1 , (KH), SFB-1454 project number 432325352 (KH). DB is supported by the Fonds National de la Recherche Luxembourg (FNR), FNR -ATTRACT program ( A14/BM/7632103 ), and by the FNR-CORE ( C18/BM/12691266 ). DB and CD receive funding through the FNRS-Televie program (No. 7.4597.19 ).The authors want to thank Sabine Kaltenhäuser for technical assistance and Prof. Thekla Cordes for helpful discussion. Alexander Heinz: Conceptualization, Methodology, Writing – original draft, Investigation, Formal analysis. Yannic Nonnenmacher: Conceptualization, Methodology, Writing – original draft, Investigation, Formal analysis. Antonia Henne: Investigation. Michelle-Amirah Khalil: Investigation. Ketlin Bejkollari: Investigation. Catherine Dostert: Investigation, Resources. Shirin Hosseini: Investigation. Oliver Goldmann: Resources. Wei He: Investigation, Writing – Review & Editing. Roberta Palorini: Methodology, Investigation. Charlène Verschueren: Investigation. Martin Korte: Resources, Writing – Review & Editing. Ferdinando Chiaradonna: Methology, Writing – Review & Editing. Eva Medina: Resources, Writing – Review & Editing. Dirk Brenner: Resources, Writing – Review & Editing. Karsten Hiller: Conceptualization, Writing – Review & Editing, Supervision. This work was funded by the Federal State of Lower Saxony, Niedersächsisches Vorab (VWZN3266), (KH), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project HI1400/3-1, (KH), SFB-1454 project number 432325352 (KH). DB is supported by the Fonds National de la Recherche Luxembourg (FNR), FNR-ATTRACT program (A14/BM/7632103), and by the FNR-CORE (C18/BM/12691266). DB and CD receive funding through the FNRS-Televie program (No. 7.4597.19).
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