Journal Article

DZNE-2022-01171

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages.

He, W. ; Henne, A. ; Lauterbach, M. ; Geißmar, E. ; Nikolka, F. ; Kho, C. ; Heinz, A. ; Dostert, C. ; Grusdat, M. ; Cordes, T. ; Härm, J. ; Goldmann, O. ; Ewen, A. ; Verschueren, C. ; Blay-Cadanet, J. ; Geffers, R. ; Garritsen, H. ; Kneiling, M. ; Holm, C. K. ; Metallo, C. M. ; Medina, E. ; Abdullah, Z. ; Latz, E.DZNE* ; Brenner, D. ; Hiller, K.

2022
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s42255-022-00565-1

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.

Keyword(s): Animals (MeSH) ; Inflammasomes (MeSH) ; Macrophages: drug effects (MeSH) ; Macrophages: metabolism (MeSH) ; Mice (MeSH) ; RAW 264.7 Cells (MeSH) ; Succinates: metabolism (MeSH) ; Succinates: pharmacology (MeSH) ; Inflammasomes ; Succinates ; itaconic acid

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Contributing Institute(s):

1. Innate Immunity in Neurodegeneration (AG Latz ; AG Latz)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2022

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF >= 15 ; JCR ; SCOPUS ; Web of Science Core Collection

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