Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages - Datasets and figures

Since its discovery in inflammatory macrophages, itaconate has attracted much attention due to its anti-microbial and immunomodulatory activity. However, instead of investigating itaconate itself, most studies employed 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 TCA 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 IL-6 and IL-12 secretion and an increase of CXCL10 production in a NRF2- and ATF3-independent manner. We show that neither a treatment with mesaconate nor itaconate impairs IL-1β secretion and inflammasome activation. In summary, our results identify mesaconate as a novel immunomodulatory metabolite in macrophages, which interferes to a lesser extent with cellular metabolism than itaconate.