Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages

Wei He, Antonia Henne, Mario Lauterbach, Eike Geißmar, Fabian Nikolka, Celia Kho, Alexander Heinz, Catherine Dostert, Melanie Grusdat, Thekla Cordes, Janika Härm, Oliver Goldmann, Anouk Ewen, Charlène Verschueren, Julia Blay-Cadanet, Robert Geffers, Hendrikus Garritsen, Manfred Kneiling, Christian K. Holm, Christian M. MetalloEva Medina, Zeinab Abdullah, Eicke Latz, Dirk Brenner, Karsten Hiller*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)524-533
Number of pages10
JournalNature Metabolism
Volume4
Issue number5
DOIs
Publication statusPublished - May 2022

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