Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function, cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because of the disturbance in the Krebs cycle is itaconate, which is derived from cis-aconitate by the enzyme cis-aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1). This Review focuses on itaconate’s emergence as a key immunometabolite with diverse roles in immunity and inflammation. These roles include inhibition of succinate dehydrogenase (which controls levels of succinate, a metabolite with multiple roles in inflammation), inhibition of glycolysis at multiple levels (which will limit inflammation), activation of the antiinflammatory transcription factors Nrf2 and ATF3, and inhibition of the NLRP3 inflammasome. Itaconate and its derivatives have antiinflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis, pointing to possible itaconate-based therapeutics for a range of inflammatory diseases. This intriguing metabolite continues to yield fascinating insights into the role of metabolic reprogramming in host defense and inflammation.

中文翻译：

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衣康酸盐在宿主防御和炎症中的作用

暴露于包括 LPS 在内的炎症刺激的巨噬细胞经历代谢重编程以促进巨噬细胞效应器功能。这种代谢重编程支持吞噬功能、细胞因子释放和对保护性炎症反应至关重要的 ROS 产生。克雷布斯循环是所有哺乳动物细胞类型中的中心代谢途径。在活化的巨噬细胞中，克雷布斯循环中的明显中断通过几种最近被证明在免疫中具有信号传导作用的代谢物的积累来调节巨噬细胞效应器的功能。由于克雷布斯循环的干扰而在巨噬细胞中积累的一种代谢物是衣康酸，它是通过顺式酶从顺乌头酸衍生而来的。-乌头酸脱羧酶 (ACOD1)，由免疫应答基因 1 ( Irg1）。本综述重点关注衣康酸盐作为一种关键免疫代谢物的出现，在免疫和炎症中具有多种作用。这些作用包括抑制琥珀酸脱氢酶（控制琥珀酸水平，一种在炎症中具有多种作用的代谢物），在多个水平上抑制糖酵解（这将限制炎症），激活抗炎转录因子 Nrf2 和 ATF3，以及抑制NLRP3 炎症小体。衣康酸盐及其衍生物在脓毒症、病毒感染、银屑病、痛风、缺血/再灌注损伤和肺纤维化的临床前模型中具有抗炎作用，这表明基于衣康酸盐的治疗可能用于一系列炎症性疾病。