Succinate and inosine coordinate innate immune response to bacterial infection.
Succinate and inosine coordinate innate immune response to bacterial infection.
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琥珀酸和肌苷协调对细菌感染的先天免疫反应。
DOI：
10.1371/journal.ppat.1010796
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发表时间：
2022-08
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
巨噬细胞限制细菌感染，部分是通过刺激吞噬作用，部分是通过刺激细胞因子和补体成分的释放。在此，我们用脂多糖（LPS）和一种细菌病原体处理巨噬细胞，结果表明，细胞因子白细胞介素 - 1β（IL - 1β）的表达和细菌吞噬作用在处理后8至12小时增加至短暂峰值，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，琥珀酸盐的细胞浓度与IL - 1β之间，以及肌苷的细胞浓度与C3之间存在相关性。这可能涉及一种调节反馈机制，即琥珀酸盐和肌苷通过与脯氨酰羟化酶的竞争性相互作用，分别刺激和抑制缺氧诱导因子 - 1α（HIF - 1α）。此外，LPS刺激的巨噬细胞中肌苷水平的升高与单磷酸腺苷的积累有关，并且外源性肌苷可提高感染细菌病原体的小鼠和罗非鱼的存活率。这些数据的意义在于，它们提示了预防、控制或治疗细菌感染的潜在治疗手段。
细菌感染仍然是主要死因之一，尤其是在抗生素储备耗尽，抗生素耐药病例不断增加的情况下。因此，需要新的方法来控制细菌感染。在此，我们报告一种基于代谢的方法，用于调控对抗细菌感染的免疫反应。我们发现，针对细菌感染的先天免疫反应由两个阶段构成，即先天细胞免疫和先天体液免疫。这两个阶段由两种代谢物，即肌苷和琥珀酸盐交替调节。琥珀酸盐促进炎症细胞因子IL - 1β的产生，而肌苷则以时间依赖的方式下调IL - 1β的表达，但增加补体成分3的表达。这种两阶段先天免疫反应对于清除细菌感染是必需的，这是一个新现象，并通过用致病菌对小鼠和鱼类进行体内攻毒实验，同时结合使用琥珀酸盐或肌苷得到了证实。我们还报告了一种新机制，即琥珀酸盐和肌苷竞争性调节HIF - 1α的激活。因此，我们的研究提出了一种新的免疫反应反馈机制，并且肌苷可能是一种调节针对细菌感染的免疫反应的潜在代谢物。
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. Bacterial infection is still one of the primary causes of death, especially in the context of exhausted antibiotic reservoir to the growing cases of antibiotic resistance. Novel approach to manage bacterial infection is required. Here, we report a metabolism-based approach to manage immune response to fight against bacterial infection. We find that innate immune response to bacterial infection is constituted with two phases, namely innate cellular immunity and innate humoral immunity. The two phases are interchangeably regulated by two metabolites, inosine and succinate. Succinate promotes the production of inflammatory cytokines IL-1β while inosine downregulates IL-1β expression but increases complement component 3 expression in a time-dependent manner. This is a novel phenomenon that this two-phases innate immune response is required to clear bacterial infection, and is confirmed by the in vivo challenge of mice and fish with pathogenic bacteria in combination of succinate or inosine. We also report a novel mechanism that succinate and inosine competitively regulate HIF-1α activation. Thus, our study presents a novel feedback mechanism of immune response, and inosine could be a potential metabolite in tuning immune response towards bacterial infection.
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