Institute of Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
FAU Profile Center Immunomedicine (FAU I-MED), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Front Immunol. 2024 Feb 28;15:1352165. doi: 10.3389/fimmu.2024.1352165. eCollection 2024.
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.
免疫细胞的激活触发信号级联反应，导致转录重编程，但也强烈影响细胞的代谢活性，为炎症和增殖反应提供能量和生物分子。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作用生成免疫代谢物衣康酸。衣康酸具有抗微生物和免疫调节活性，使其成为具有吸引力的内源性效应代谢物，可抵抗感染并抑制炎症。在这里，我们首先总结了诱导巨噬细胞中 ACOD1 表达的途径和刺激物。然后，本综述的重点在于衣康酸及其合成衍生物和内源性异构体调节免疫细胞信号转导和代谢途径的机制。已经揭示了多个靶标，从抑制酶到半胱氨酸或赖氨酸残基上许多蛋白质的翻译后修饰。信号蛋白如 STING、SYK、JAK1、RIPK3 和 KEAP1、转录调节剂（如 Tet2、TFEB）和炎症小体成分（NLRP3、GSDMD）的调节为 ACOD1-衣康酸途径的免疫调节作用提供了生化基础。虽然该领域在感染和炎症模型中强烈研究了衣康酸对巨噬细胞的控制，但中性粒细胞现在已经成为衣康酸的产生细胞和靶细胞。此外，内源性衣康酸以及外源性添加的衣康酸和衍生物对适应性免疫反应的调节可以分别通过对 T 细胞和抗原呈递细胞的直接和间接影响来介导。总之，迄今为止，关于 ACOD1-衣康酸的研究揭示了其在多种免疫细胞信号通路中的相关性，这为宿主防御和炎症的潜在治疗或预防干预提供了机会。
