PDF(Pubmed)
Abstract：
Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell\'s metabolic activity to provide energy and biomolecules for inflammatory and proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns and cytokines upregulate expression of the enzyme ACOD1 that generates the immune-metabolite itaconate by decarboxylation of the TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well as immunomodulatory activities, which makes it attractive as endogenous effector metabolite fighting infection and restraining inflammation. Here, we first summarize the pathways and stimuli inducing ACOD1 expression in macrophages. The focus of the review then lies on the mechanisms by which itaconate, and its synthetic derivatives and endogenous isomers, modulate immune cell signaling and metabolic pathways. Multiple targets have been revealed, from inhibition of enzymes to the post-translational modification of many proteins at cysteine or lysine residues. The modulation of signaling proteins like STING, SYK, JAK1, RIPK3 and KEAP1, transcription regulators (e.g. Tet2, TFEB) and inflammasome components (NLRP3, GSDMD) provides a biochemical basis for the immune-regulatory effects of the ACOD1-itaconate pathway. While the field has intensely studied control of macrophages by itaconate in infection and inflammation models, neutrophils have now entered the scene as producers and cellular targets of itaconate. Furthermore, regulation of adaptive immune responses by endogenous itaconate, as well as by exogenously added itaconate and derivatives, can be mediated by direct and indirect effects on T cells and antigen-presenting cells, respectively. Taken together, research in ACOD1-itaconate to date has revealed its relevance in diverse immune cell signaling pathways, which now provides opportunities for potential therapeutic or preventive manipulation of host defense and inflammation.
摘要：
免疫细胞激活触发信号级联，导致转录重编程，但也强烈影响细胞的代谢活动，为炎症和增殖反应提供能量和生物分子。由微生物病原体相关分子模式和细胞因子激活的巨噬细胞上调酶ACOD1的表达，该酶通过TCA循环代谢物顺式乌头酸的脱羧产生免疫代谢物衣康酸酯。衣康酸具有抗微生物和免疫调节活性，这使得它具有吸引力作为内源性效应代谢物对抗感染和抑制炎症。这里,我们首先总结了诱导巨噬细胞ACOD1表达的途径和刺激。审查的重点在于衣康酸酯的机制，及其合成衍生物和内源性异构体，调节免疫细胞信号传导和代谢途径。已经发现了多个目标,从酶的抑制到许多蛋白质在半胱氨酸或赖氨酸残基的翻译后修饰。像STING这样的信号蛋白的调节，SYK,JAK1，RIPK3和KEAP1，转录调节因子（例如Tet2，TFEB）和炎性体成分（NLRP3，GSDMD）为ACOD1-衣康酸途径的免疫调节作用提供了生化基础。虽然该领域已经深入研究了衣康酸在感染和炎症模型中对巨噬细胞的控制，中性粒细胞现在已经作为衣康酸酯的生产者和细胞靶标进入现场。此外，内源性衣康酸对适应性免疫反应的调节，以及通过外源添加的衣康酸酯和衍生物，可以通过对T细胞和抗原呈递细胞的直接和间接作用来介导，分别。一起来看,迄今为止，ACOD1-衣康酸的研究已经揭示了它在不同免疫细胞信号通路中的相关性，现在为宿主防御和炎症的潜在治疗或预防性操作提供了机会。
