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000164641 037__ $$aDZNE-2022-01171
000164641 041__ $$aEnglish
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000164641 1001_ $$aHe, Wei$$b0
000164641 245__ $$aMesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages.
000164641 260__ $$a[London]$$bSpringer Nature$$c2022
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000164641 520__ $$aSince its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity1-3. However, instead of investigating itaconate itself, most studies used derivatized forms of itaconate and thus the role of non-derivatized itaconate needs to be scrutinized. Mesaconate, a metabolite structurally very close to itaconate, has never been implicated in mammalian cells. Here we show that mesaconate is synthesized in inflammatory macrophages from itaconate. We find that both, non-derivatized itaconate and mesaconate dampen the glycolytic activity to a similar extent, whereas only itaconate is able to repress tricarboxylic acid cycle activity and cellular respiration. In contrast to itaconate, mesaconate does not inhibit succinate dehydrogenase. Despite their distinct impact on metabolism, both metabolites exert similar immunomodulatory effects in pro-inflammatory macrophages, specifically a reduction of interleukin (IL)-6 and IL-12 secretion and an increase of CXCL10 production in a manner that is independent of NRF2 and ATF3. We show that a treatment with neither mesaconate nor itaconate impairs IL-1β secretion and inflammasome activation. In summary, our results identify mesaconate as an immunomodulatory metabolite in macrophages, which interferes to a lesser extent with cellular metabolism than itaconate.
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000164641 650_7 $$2NLM Chemicals$$aInflammasomes
000164641 650_7 $$2NLM Chemicals$$aSuccinates
000164641 650_7 $$0Q4516562YH$$2NLM Chemicals$$aitaconic acid
000164641 650_2 $$2MeSH$$aAnimals
000164641 650_2 $$2MeSH$$aInflammasomes
000164641 650_2 $$2MeSH$$aMacrophages: drug effects
000164641 650_2 $$2MeSH$$aMacrophages: metabolism
000164641 650_2 $$2MeSH$$aMice
000164641 650_2 $$2MeSH$$aRAW 264.7 Cells
000164641 650_2 $$2MeSH$$aSuccinates: metabolism
000164641 650_2 $$2MeSH$$aSuccinates: pharmacology
000164641 7001_ $$00000-0001-6870-5312$$aHenne, Antonia$$b1
000164641 7001_ $$aLauterbach, Mario$$b2
000164641 7001_ $$aGeißmar, Eike$$b3
000164641 7001_ $$aNikolka, Fabian$$b4
000164641 7001_ $$aKho, Celia$$b5
000164641 7001_ $$aHeinz, Alexander$$b6
000164641 7001_ $$aDostert, Catherine$$b7
000164641 7001_ $$aGrusdat, Melanie$$b8
000164641 7001_ $$aCordes, Thekla$$b9
000164641 7001_ $$aHärm, Janika$$b10
000164641 7001_ $$aGoldmann, Oliver$$b11
000164641 7001_ $$aEwen, Anouk$$b12
000164641 7001_ $$aVerschueren, Charlène$$b13
000164641 7001_ $$aBlay-Cadanet, Julia$$b14
000164641 7001_ $$00000-0003-4409-016X$$aGeffers, Robert$$b15
000164641 7001_ $$aGarritsen, Hendrikus$$b16
000164641 7001_ $$aKneiling, Manfred$$b17
000164641 7001_ $$00000-0002-2655-3362$$aHolm, Christian K$$b18
000164641 7001_ $$00000-0003-2404-3040$$aMetallo, Christian M$$b19
000164641 7001_ $$aMedina, Eva$$b20
000164641 7001_ $$aAbdullah, Zeinab$$b21
000164641 7001_ $$0P:(DE-2719)2000062$$aLatz, Eicke$$b22$$udzne
000164641 7001_ $$00000-0001-8979-1045$$aBrenner, Dirk$$b23
000164641 7001_ $$00000-0001-9322-5820$$aHiller, Karsten$$b24
000164641 773__ $$0PERI:(DE-600)2933873-6$$a10.1038/s42255-022-00565-1$$gVol. 4, no. 5, p. 524 - 533$$n5$$p524 - 533$$tNature metabolism$$v4$$x2522-5812$$y2022
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