[en] Since its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity1-3. However, instead of investigating itaconate itself, most studies used derivatized forms of itaconate and thus the role of non-derivatized itaconate needs to be scrutinized. Mesaconate, a metabolite structurally very close to itaconate, has never been implicated in mammalian cells. Here we show that mesaconate is synthesized in inflammatory macrophages from itaconate. We find that both, non-derivatized itaconate and mesaconate dampen the glycolytic activity to a similar extent, whereas only itaconate is able to repress tricarboxylic acid cycle activity and cellular respiration. In contrast to itaconate, mesaconate does not inhibit succinate dehydrogenase. Despite their distinct impact on metabolism, both metabolites exert similar immunomodulatory effects in pro-inflammatory macrophages, specifically a reduction of interleukin (IL)-6 and IL-12 secretion and an increase of CXCL10 production in a manner that is independent of NRF2 and ATF3. We show that a treatment with neither mesaconate nor itaconate impairs IL-1β secretion and inflammasome activation. In summary, our results identify mesaconate as an immunomodulatory metabolite in macrophages, which interferes to a lesser extent with cellular metabolism than itaconate.
Disciplines :
Immunology & infectious disease
Author, co-author :
He, Wei; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany
Henne, Antonia ; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany
Lauterbach, Mario; Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn, Germany
Geißmar, Eike; Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn, Germany
Nikolka, Fabian; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany
Kho, Celia; Institute of Experimental Immunology, University Hospital Bonn, University of Bonn, Bonn, Germany
Heinz, Alexander; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany
Dostert, Catherine; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology and Genetics, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belval, Luxembourg
Grusdat, Melanie; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology and Genetics, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belval, Luxembourg
Cordes, Thekla; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany ; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA ; Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
Härm, Janika; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology and Genetics, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belval, Luxembourg
Goldmann, Oliver; Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
Ewen, Anouk; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology and Genetics, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belval, Luxembourg
Verschueren, Charlène; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Immunology and Genetics, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belval, Luxembourg
Blay-Cadanet, Julia; Department of Biomedicine, Aarhus University, Aarhus, Denmark
Geffers, Robert ; Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
Garritsen, Hendrikus; Institute of Transfusion Medicine, Klinikum Braunschweig, Braunschweig, Germany ; Fraunhofer Institute for Surface Engineering and Thin Films IST, Braunschweig, Germany
Kneiling, Manfred; Department of Dermatology, Eberhard Karls University, Tübingen, Germany ; Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
Holm, Christian K ; Department of Biomedicine, Aarhus University, Aarhus, Denmark
Metallo, Christian M ; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA ; Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
Medina, Eva; Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
Abdullah, Zeinab; Institute of Experimental Immunology, University Hospital Bonn, University of Bonn, Bonn, Germany ; Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran
Latz, Eicke ; Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases, Bonn, Germany ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA ; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway
BRENNER, Dirk ; University of Luxembourg ; Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg ; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark
Hiller, Karsten ; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany. karsten.hiller@tu-braunschweig.de
Deutsche Forschungsgemeinschaft Fonds National de la Recherche Luxembourg
Funding text :
This work is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) project HI1400/3-1 (to K.H.), SFB-1403 project 414786233 (to E.L.), SFB-1454 project 432325352 (to Z.A., E.L. and K.H.) and ImmunoSensation2 EXC2151 project 390873048 (to Z.A. and E.L.). D.B. is supported by the FNR-ATTRACT programme (A14/BM/7632103), and by the FNR-CORE (C18/BM/12691266). D.B. and C.D. receive funding through the FNRS-Televie programme (7.4597.19). We thank the NIH Common Fund Metabolite Standards Synthesis Core (NHLBI contract no. HHSN268201300022C) for providing isotopic labelled itaconate ([U-13C5]itaconate).This work is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) project HI1400/3-1 (to K.H.), SFB-1403 project 414786233 (to E.L.), SFB-1454 project 432325352 (to Z.A., E.L. and K.H.) and ImmunoSensation2 EXC2151 project 390873048 (to Z.A. and E.L.). D.B. is supported by the FNR-ATTRACT programme (A14/BM/7632103), and by the FNR-CORE (C18/BM/12691266). D.B. and C.D. receive funding through the FNRS-Televie programme (7.4597.19). We thank the NIH Common Fund Metabolite Standards Synthesis Core (NHLBI contract no. HHSN268201300022C) for providing isotopic labelled itaconate ([U-C]itaconate). 13 5
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