Mitochondrial choline metabolism in innate immunity

先天免疫中的线粒体胆碱代谢

• 批准号: RGPIN-2021-03503
• 负责人: Fullerton, Morgan
• 金额: $ 2.62万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744318
• 关键词: Mitochondrial; choline; metabolism; innate; immunity

Choline is a nutrient that plays an important role in all cells. Our research wants to understand how aspects of immunity and metabolism are linked. Immune cells called macrophages are constantly surveying for an immune trigger such as bacteria or damaged cells. When they see a trigger, they can turn on specific programs that are meant to either control an infection or repair cellular damage. We have shown that macrophage cells can become over-activated and inflammatory (angry) when choline cannot be taken into the cell (which might actually be good for something like infection). On the flip side, when these cells encounter an immune trigger, they up-regulate choline transport and metabolism (which again, might be a necessary process). This has been the focus of our previous NSERC-funded work. But we do not think that is the whole story. Choline is made into membranes in all types of cells and this is a big part of its importance. Choline can also enter the powerhouse of the cell (mitochondria) where it can then affect how DNA is read and interpreted, but this was only thought to happen in the liver and kidney. Based on new evidence from our lab and others, we think that choline can enter and be processed in the mitochondria of immune cells, but how, why and when this happens is still a mystery. We are aiming to test 1) how macrophage cells take up choline into their mitochondria, 2) if/how this special uptake of choline into the mitochondria can change with different immune triggers and 3) what are the overall consequences of this process (what pathways and processes are affected). We have uncovered an important role for choline metabolism in controlling inflammation and vice versa. However, our recent observations that choline is taken into the mitochondria of immune cells has identified a previously unexplored and unanticipated pathway in these important cells. This basic discovery-based research could highlight a new regulator of immune cells and extend our understanding of how the immune system and metabolism are linked.

胆碱是一种在所有细胞中发挥重要作用的营养物质。我们的研究想要了解免疫和新陈代谢方面是如何联系在一起的。被称为巨噬细胞的免疫细胞不断地检测细菌或受损细胞等免疫触发因素。当他们看到触发器时，他们可以打开特定的程序，这些程序旨在控制感染或修复细胞损伤。我们已经证明，当胆碱不能进入细胞时，巨噬细胞会变得过度激活和炎症(愤怒)(这实际上可能对感染等疾病有好处)。另一方面，当这些细胞遇到免疫触发时，它们会上调胆碱的运输和代谢(这可能也是一个必要的过程)。这是我们之前由NSERC资助的工作的重点。但我们认为这并不是事情的全部。胆碱在所有类型的细胞中都被制成膜，这是其重要性的一大部分。胆碱也可以进入细胞的发动机(线粒体)，在那里它可以影响DNA的读取和解释，但这被认为只发生在肝脏和肾脏。根据我们实验室和其他实验室的新证据，我们认为胆碱可以进入免疫细胞的线粒体并被处理，但这种情况是如何发生的，为什么以及何时发生，仍然是一个谜。我们的目标是测试1)巨噬细胞如何将胆碱摄取到它们的线粒体中，2)这种特殊的胆碱摄取是否/如何随着不同的免疫触发而改变，以及3)这个过程的总体后果是什么(什么途径和过程受到影响)。我们发现了胆碱代谢在控制炎症中的重要作用，反之亦然。然而，我们最近观察到，胆碱被带入免疫细胞的线粒体，这在这些重要细胞中发现了一条以前未被探索和预料到的途径。这项以发现为基础的研究可能会突出免疫细胞的一种新的调节因素，并扩大我们对免疫系统和新陈代谢如何联系的理解。