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Mesaconate Is Synthesized From Itaconate and Exerts Immunomodulatory Effects in Macrophages Publisher Pubmed



He W1 ; Henne A1 ; Lauterbach M2 ; Geimar E2 ; Nikolka F1 ; Kho C3 ; Heinz A1 ; Dostert C4, 5 ; Grusdat M4, 5 ; Cordes T1, 6, 7 ; Harm J1, 4, 5 ; Goldmann O8 ; Ewen A4, 5 ; Verschueren C4, 5 Show All Authors
Authors
  1. He W1
  2. Henne A1
  3. Lauterbach M2
  4. Geimar E2
  5. Nikolka F1
  6. Kho C3
  7. Heinz A1
  8. Dostert C4, 5
  9. Grusdat M4, 5
  10. Cordes T1, 6, 7
  11. Harm J1, 4, 5
  12. Goldmann O8
  13. Ewen A4, 5
  14. Verschueren C4, 5
  15. Blaycadanet J9
  16. Geffers R10
  17. Garritsen H11, 12
  18. Kneiling M13, 14
  19. Holm CK9
  20. Metallo CM6, 7
  21. Medina E8
  22. Abdullah Z3, 15
  23. Latz E2, 16, 17, 18
  24. Brenner D4, 5, 19
  25. Hiller K1
Show Affiliations
Authors Affiliations
  1. 1. Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universitat Braunschweig, Braunschweig, Germany
  2. 2. Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn, Germany
  3. 3. Institute of Experimental Immunology, University Hospital Bonn, University of Bonn, Bonn, Germany
  4. 4. Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
  5. 5. Immunology and Genetics, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belval, Luxembourg
  6. 6. Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States
  7. 7. Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, United States
  8. 8. Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
  9. 9. Department of Biomedicine, Aarhus University, Aarhus, Denmark
  10. 10. Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
  11. 11. Institute of Transfusion Medicine, Klinikum Braunschweig, Braunschweig, Germany
  12. 12. Fraunhofer Institute for Surface Engineering and Thin Films IST, Braunschweig, Germany
  13. 13. Department of Dermatology, Eberhard Karls University, Tubingen, Germany
  14. 14. Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tubingen, Germany
  15. 15. Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran
  16. 16. German Center for Neurodegenerative Diseases, Bonn, Germany
  17. 17. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, United States
  18. 18. Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway
  19. 19. Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark

Source: Nature Metabolism Published:2022


Abstract

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. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
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