Abstract：
Immunometabolism has been unveiled in the last decade to play a major role in controlling macrophage metabolism and inflammation. There has been a constant effort to understand the immunomodulating properties of regulated metabolites during inflammation with the aim of controlling and re-wiring aberrant macrophages in inflammatory diseases. M-CSF and GM-CSF-differentiated macrophages play a key role in mounting successful innate immune responses. When a resolution phase is not achieved however, GM-CSF macrophages contribute substantially more towards an adverse inflammatory milieu than M-CSF macrophages, consequently driving disease progression. Whether there are specific immunometabolites that determine the homoeostatic or inflammatory nature of M-CSF and GM-CSF-differentiated macrophages is still unknown. As such, we performed metabolomics analysis on LPS and IL-4-stimulated M-CSF and GM-CSF-differentiated human macrophages to identify differentially accumulating metabolites. Adenine was distinguished as a metabolite significantly higher in M-CSF-differentiated macrophages after both LPS or IL-4 stimulation. Human macrophages treated with adenine before LPS stimulation showed a reduction in inflammatory gene expression, cytokine secretion and surface marker expression. Adenine caused macrophages to become more quiescent by lowering glycolysis and OXPHOS which resulted in reduced ATP production. Moreover, typical metabolite changes seen during LPS-induced macrophage metabolic reprogramming were absent in the presence of adenine. Phosphorylation of metabolic signalling proteins AMPK, p38 MAPK and AKT were not responsible for the suppressed metabolic activity of adenine-treated macrophages. Altogether, in this study we highlight the immunomodulating capacity of adenine in human macrophages and its function in driving cellular quiescence.
摘要：
在过去的十年中，免疫代谢在控制巨噬细胞代谢和炎症中起着重要作用。为了控制和重新连接炎性疾病中的异常巨噬细胞，人们一直在努力了解炎症过程中受调节代谢物的免疫调节特性。M-CSF和GM-CSF分化的巨噬细胞在成功的先天免疫应答中起关键作用。然而，当没有达到分辨率阶段时，GM-CSF巨噬细胞比M-CSF巨噬细胞对不良炎症环境的贡献更大，从而推动疾病进展。是否存在确定M-CSF和GM-CSF分化的巨噬细胞的稳态或炎症性质的特异性免疫代谢物仍然是未知的。因此，我们对LPS和IL-4刺激的M-CSF和GM-CSF分化的人巨噬细胞进行了代谢组学分析,以鉴定差异积累的代谢物.在LPS或IL-4刺激后，腺嘌呤在M-CSF分化的巨噬细胞中明显更高。在LPS刺激前用腺嘌呤处理的人巨噬细胞显示炎症基因表达减少，细胞因子分泌和表面标志物表达。腺嘌呤通过降低糖酵解和OXPHOS导致巨噬细胞变得更加静止，从而导致ATP产生减少。此外，在存在腺嘌呤的情况下，在LPS诱导的巨噬细胞代谢重编程过程中观察到的典型代谢物变化不存在。代谢信号蛋白AMPK的磷酸化,p38MAPK和AKT对腺嘌呤处理的巨噬细胞的代谢活性抑制没有作用。总之,在这项研究中，我们强调了腺嘌呤在人巨噬细胞中的免疫调节能力及其在驱动细胞静止中的作用。
