Since its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity^1,2,3. 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.

自从在炎症巨噬细胞中发现以来，衣康酸因其抗菌和免疫调节活性而备受关注^1,2,3。然而，大多数研究没有研究衣康酸本身，而是使用衣康酸的衍生形式，因此需要仔细研究非衍生化的衣康酸的作用。中康酸是一种结构上与衣康酸非常接近的代谢物，从未与哺乳动物细胞有关。在这里，我们表明中康酸是在炎症巨噬细胞中由衣康酸合成的。我们发现，非衍生化的衣康酸和中康酸都以相似的程度抑制糖酵解活性，而只有衣康酸能够抑制三羧酸循环活性和细胞呼吸。与衣康酸相反，中康酸不抑制琥珀酸脱氢酶。尽管它们对代谢有不同的影响，但这两种代谢物在促炎巨噬细胞中发挥相似的免疫调节作用，特别是减少白细胞介素 (IL)-6 和 IL-12 的分泌以及以独立于 NRF2 和 ATF3 的方式增加 CXCL10 的产生。我们发现，既不使用中康酸也不使用衣康酸的治疗会损害 IL-1β 的分泌和炎症小体的激活。总之，我们的结果将中康酸确定为巨噬细胞中的免疫调节代谢物，与衣康酸相比，其对细胞代谢的干扰程度较小。