Morgridge Institute for Research, Madison, WI, USA.
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
Nat Metab. 2022 Mar;4(3):389-403. doi: 10.1038/s42255-022-00550-8. Epub 2022 Mar 28.
Neutrophils are cells at the frontline of innate immunity that can quickly activate effector functions to eliminate pathogens upon stimulation. However, little is known about the metabolic adaptations that power these functions. Here we show rapid metabolic alterations in neutrophils upon activation, particularly drastic reconfiguration around the pentose phosphate pathway, which is specifically and quantitatively coupled to an oxidative burst. During this oxidative burst, neutrophils switch from glycolysis-dominant metabolism to a unique metabolic mode termed 'pentose cycle', where all glucose-6-phosphate is diverted into oxidative pentose phosphate pathway and net flux through upper glycolysis is reversed to allow substantial recycling of pentose phosphates. This reconfiguration maximizes NADPH yield to fuel superoxide production via NADPH oxidase. Disruptions of pentose cycle greatly suppress oxidative burst, the release of neutrophil extracellular traps and pathogen killing by neutrophils. Together, these results demonstrate the remarkable metabolic flexibility of neutrophils, which is essential for their functions as the first responders in innate immunity.
中性粒细胞是先天免疫的前沿细胞，在受到刺激后可以迅速激活效应功能来消灭病原体。然而，人们对支持这些功能的代谢适应知之甚少。在这里，我们展示了中性粒细胞在激活时的快速代谢改变，特别是戊糖磷酸途径的剧烈重构，该途径与氧化爆发特异性和定量偶联。在这个氧化爆发过程中，中性粒细胞从糖酵解主导的代谢转变为一种独特的代谢模式，称为“戊糖循环”，其中所有的葡萄糖-6-磷酸都被转移到氧化戊糖磷酸途径中，而上游糖酵解的净通量被反转，从而允许戊糖磷酸的大量循环利用。这种重构最大限度地增加了 NADPH 的产量，通过 NADPH 氧化酶为超氧化物的产生提供燃料。戊糖循环的中断会大大抑制氧化爆发、中性粒细胞胞外陷阱的释放以及中性粒细胞对病原体的杀伤作用。总之，这些结果表明中性粒细胞具有显著的代谢灵活性，这对它们作为先天免疫的第一道防线的功能至关重要。
