Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

中文翻译：

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琥珀酸酯是巨噬细胞中炎症诱导的免疫调节代谢产物。

免疫代谢揭示了细胞代谢在控制免疫细胞表型和功能中的关键作用。巨噬细胞是支持多种炎性疾病进展的关键免疫细胞，已被很好地描述为在激活后会经历大量的代谢重建。琥珀酸免疫代谢物尤其引起了广泛关注，并成为巨噬细胞反应和炎症的重要调节剂。琥珀酸酯最初被描述为通过不同途径支持炎症的代谢产物。最近，研究表明琥珀酸酯及其受体SUCNR1也可以抑制免疫反应。这些明显的矛盾效应可能是由于特定的实验设置，尤其是使用不同的琥珀酸酯形式。因此，我们比较了不同的琥珀酸盐形式和以前用于研究琥珀酸盐免疫调节的受体小鼠模型的表型和功能作用。在这里，我们表明琥珀酸酯可以抑制炎症介质IL-6，肿瘤坏死因子（TNF）和一氧化氮（NO）的分泌，并抑制炎症巨噬细胞的Il1b mRNA表达以SUCNR1独立方式表达。我们还观察到巨噬细胞SUCNR1缺乏导致不增加外源性琥珀酸盐而导致的炎症反应增强。尽管我们的研究没有揭示琥珀酸如何引发不同炎症反应的新机制，但确实表明琥珀酸及其受体SUCNR1在巨噬细胞中的炎症作用明显取决于环境。