The role of itaconate in host defense and inflammation.
The role of itaconate in host defense and inflammation.
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衣康酸在宿主防御和炎症中的作用。
DOI：
10.1172/jci148548
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发表时间：
2022-01-18
期刊：
影响因子：
--
通讯作者：
O'Neill LA
中科院分区：
文献类型：
--
作者：
Peace CG;O'Neill LA
巨噬细胞暴露在包括内毒素在内的炎性刺激下，进行代谢重编程以促进巨噬细胞效应器的功能。这种代谢重编程支持对保护性炎症反应至关重要的吞噬功能、细胞因子释放和ROS产生。Krebs周期是所有哺乳动物细胞类型的中心代谢途径。在激活的巨噬细胞中，Krebs循环中的明显断裂通过积累最近被证明在免疫中具有信号作用的几种代谢物来调节巨噬细胞效应器的功能。由于Krebs循环的干扰，在巨噬细胞中积聚的一种代谢物是衣康酸，它是由免疫反应基因1(IRG1)编码的顺式附子脱羧酶(ACOD1)产生的。本文主要介绍衣康酸作为一种重要的免疫代谢产物在免疫和炎症中的作用。这些作用包括抑制琥珀酸脱氢酶(控制琥珀酸的水平，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。衣康酸及其衍生物在脓毒症、病毒感染、牛皮癣、痛风、缺血/再灌注损伤和肺纤维化等临床前模型中具有抗炎作用，表明衣康酸可能用于一系列炎症性疾病的治疗。这种耐人寻味的代谢物继续对代谢重新编程在宿主防御和炎症中的作用产生迷人的见解。
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.