Arthritis as a model to define immunometabolism pathways to control inflammation

中性粒细胞(PMN)在生理和病理中发挥着重要的作用，但我们对PMN执行这些功能的代谢需求知之甚少。我的计划使用抗原诱导的小鼠关节炎模型来研究糖酵解和氧化磷酸化(OXPHOS)之间的能量代谢平衡调控PMN在激活、迁移和生存中的功能，这些过程有助于炎症反应的有效性、持续时间和结果。将进行一系列有组织的假设驱动的实验，以(I)促进对PMN在迁移和消退炎症期间所使用的代谢途径的了解；以及(Ii)确定是否可以通过靶向PMN的能量代谢来调节炎症。最近的研究揭示了关于免疫代谢的新信息，免疫代谢被定义为免疫细胞内改变其功能的细胞内代谢途径的变化。这些研究表明，淋巴细胞、巨噬细胞和树突状细胞经历了深刻的代谢重新编程，以应对环境变化，如低氧或营养物质的可获得性，但重要的是对促炎和抗炎介质的反应。然而，这些研究大多是在体外进行的；尽管在高度受控的环境中提供了结果，但体外环境并不代表完整的生理环境。此外，基于简单地将其归类为预先武装到达执行这一功能的抗微生物细胞，在考虑免疫代谢时，PMN经常被忽视或忽视，这一立场需要重新评估。中性粒细胞从血液中招募来执行效应器功能。中性粒细胞的募集受细胞黏附分子的调节，黏附分子最初导致中性粒细胞在内皮上滚动。滚压对于PMN随后牢固地附着在容器上是必不可少的。一旦被附着，PMN就会启动爬行运动，导致这些细胞从血液迁移到组织中。在组织中执行效应功能后，PMN会发生凋亡，以促进炎症的消退。然而，如果PMN功能上调，它们有可能导致不希望看到的宿主组织损伤。另一方面，如果PMN功能下调，宿主可能会变得容易感染。因此，PMN功能的微调必须伴随代谢微调。我的计划将解决与炎症反应的启动、持续和消退相关的体内系统中PMN免疫代谢微调方面的重大知识空白。

Polymorphonuclear neutrophils (PMNs) play critical functions in physiology and pathology, but we poorly understand the metabolic requirements for PMNs to perform these functions. My program uses the model of antigen-induced arthritis in mice to investigate the concept that the balance of energy metabolism between glycolysis and oxidative phosphorylation (OXPHOS) governs PMN functions in activation, migration and survival, processes that contribute to the effectiveness, duration and outcome of the inflammatory response. A structured series of hypothesis-driven experiments will be performed to (i) advance knowledge of metabolic pathways used by PMNs in migration and during resolution of inflammation; and (ii) determine if inflammation can be modulated by targeting PMN energy metabolism. Recent studies have revealed new information about immunometabolism, defined as changes in intracellular metabolic pathways in immune cells that alter their function. These studies indicated that lymphocytes, macrophages and dendritic cells undergo profound metabolic reprogramming in response to environmental changes, such as hypoxia or nutrient availability, but importantly also in response to pro- and anti-inflammatory mediators. However, most of these studies were conducted in vitro; despite providing results in a highly controlled environment, the in vitro milieu does not represent the complete physiological environment. In addition, based on classification simply as an anti-microbial cell that arrives pre-armed to perform this function, PMNs are often overlooked or dismissed when considering immunometabolism, and this position needs to be re-evaluated. PMNs are recruited from the bloodstream to perform effector functions. Recruitment of PMNs is regulated by cell adhesion molecules that initially lead to the rolling of PMNs on the endothelium. Rolling is imperative to the subsequent firm adhesion of PMNs to the vessel. Once adhered, PMNs initiate a crawling movement that leads to the emigration of those cells from the blood to tissue. After performing effector functions in the tissue, PMNs undergo apoptosis to promote the resolution of inflammation. However, if PMN function is upregulated, they have the potential to cause undesired host tissue damage. On the other hand, if PMN function is downregulated, the host may become susceptible to infections. Therefore, fine-tuning of PMN function must be accompanied by metabolic fine-tuning. My program will address significant gaps in knowledge around fine-tuning of immunometabolism in PMN in an in vivo system relevant to the initiation, duration and resolultion of the inflammatory response.