Center for Proteomics and Metabolomics, State Key Laboratory of Bio-Control, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Higher Education Mega Center, Guangzhou, People's Republic of China.
Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, People's Republic of China.
PLoS Pathog. 2022 Aug 26;18(8):e1010796. doi: 10.1371/journal.ppat.1010796. eCollection 2022 Aug.
Macrophages restrict bacterial infection partly by stimulating phagocytosis and partly by stimulating release of cytokines and complement components. Here, we treat macrophages with LPS and a bacterial pathogen, and demonstrate that expression of cytokine IL-1β and bacterial phagocytosis increase to a transient peak 8 to 12 h post-treatment, while expression of complement component 3 (C3) continues to rise for 24 h post-treatment. Metabolomic analysis suggests a correlation between the cellular concentrations of succinate and IL-1β and of inosine and C3. This may involve a regulatory feedback mechanism, whereby succinate stimulates and inosine inhibits HIF-1α through their competitive interactions with prolyl hydroxylase. Furthermore, increased level of inosine in LPS-stimulated macrophages is linked to accumulation of adenosine monophosphate and that exogenous inosine improves the survival of bacterial pathogen-infected mice and tilapia. The implications of these data suggests potential therapeutic tools to prevent, manage or treat bacterial infections.
巨噬细胞通过刺激吞噬作用和细胞因子及补体成分的释放来部分限制细菌感染。在这里，我们用 LPS 和一种细菌病原体处理巨噬细胞，结果表明细胞因子 IL-1β 的表达和细菌的吞噬作用在处理后 8 到 12 小时内增加到一个短暂的峰值，而补体成分 3（C3）的表达在处理后 24 小时内持续上升。代谢组学分析表明，琥珀酸盐和 IL-1β的细胞浓度以及肌苷和 C3 之间存在相关性。这可能涉及一个调节反馈机制，其中琥珀酸盐通过与脯氨酰羟化酶的竞争性相互作用刺激 HIF-1α，而肌苷抑制 HIF-1α。此外，LPS 刺激的巨噬细胞中肌苷水平的增加与单磷酸腺苷的积累有关，外源性肌苷可提高细菌病原体感染小鼠和罗非鱼的存活率。这些数据表明了一些潜在的治疗工具，可以预防、管理或治疗细菌感染。
