TY  - JOUR
AU  - He, Wei
AU  - Henne, Antonia
AU  - Lauterbach, Mario
AU  - Geißmar, Eike
AU  - Nikolka, Fabian
AU  - Kho, Celia
AU  - Heinz, Alexander
AU  - Dostert, Catherine
AU  - Grusdat, Melanie
AU  - Cordes, Thekla
AU  - Härm, Janika
AU  - Goldmann, Oliver
AU  - Ewen, Anouk
AU  - Verschueren, Charlène
AU  - Blay-Cadanet, Julia
AU  - Geffers, Robert
AU  - Garritsen, Hendrikus
AU  - Kneiling, Manfred
AU  - Holm, Christian K
AU  - Metallo, Christian M
AU  - Medina, Eva
AU  - Abdullah, Zeinab
AU  - Latz, Eicke
AU  - Brenner, Dirk
AU  - Hiller, Karsten
TI  - Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages.
JO  - Nature metabolism
VL  - 4
IS  - 5
SN  - 2522-5812
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2022-01171
SP  - 524 - 533
PY  - 2022
AB  - 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.
KW  - Animals
KW  - Inflammasomes
KW  - Macrophages: drug effects
KW  - Macrophages: metabolism
KW  - Mice
KW  - RAW 264.7 Cells
KW  - Succinates: metabolism
KW  - Succinates: pharmacology
KW  - Inflammasomes (NLM Chemicals)
KW  - Succinates (NLM Chemicals)
KW  - itaconic acid (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9744384
C6  - pmid:35655024
DO  - DOI:10.1038/s42255-022-00565-1
UR  - https://pub.dzne.de/record/164641
ER  -