Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.

衣康酸盐是炎性巨噬细胞中上调最严重的代谢物之一，已被证明具有免疫调节特性。在这里，我们表明衣康酸盐通过抑制琥珀酸脱氢酶 （SDH） 促进 I 型干扰素的产生。使用药理学和遗传学方法，我们表明内源性或外源性衣康酸盐对 SDH 的抑制导致双链线粒体 RNA （mtRNA） 释放，这取决于 VDAC1 形成的线粒体孔。此外，双链 RNA 传感器 MDA5 和 RIG-I 是响应衣康酸盐对 SDH 抑制的 IFNβ 产生所必需的。总的来说，我们的数据表明，衣康酸盐对 SDH 的抑制将 TCA 循环调节与通过 mtRNA 释放产生的 I 型干扰素联系起来。