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Autophagy-Dependent Generation of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation
Immunity ( IF 32.4 ) Pub Date : 2017-09-12 , DOI: 10.1016/j.immuni.2017.08.005
Thomas Riffelmacher , Alexander Clarke , Felix C. Richter , Amanda Stranks , Sumeet Pandey , Sara Danielli , Philip Hublitz , Zhanru Yu , Errin Johnson , Tobias Schwerd , James McCullagh , Holm Uhlig , Sten Eirik W. Jacobsen , Anna Katharina Simon

Neutrophils are critical and short-lived mediators of innate immunity that require constant replenishment. Their differentiation in the bone marrow requires extensive cytoplasmic and nuclear remodeling, but the processes governing these energy-consuming changes are unknown. While previous studies show that autophagy is required for differentiation of other blood cell lineages, its function during granulopoiesis has remained elusive. Here, we have shown that metabolism and autophagy are developmentally programmed and essential for neutrophil differentiation in vivo. Atg7-deficient neutrophil precursors had increased glycolytic activity but impaired mitochondrial respiration, decreased ATP production, and accumulated lipid droplets. Inhibiting autophagy-mediated lipid degradation or fatty acid oxidation alone was sufficient to cause defective differentiation, while administration of fatty acids or pyruvate for mitochondrial respiration rescued differentiation in autophagy-deficient neutrophil precursors. Together, we show that autophagy-mediated lipolysis provides free fatty acids to support a mitochondrial respiration pathway essential to neutrophil differentiation.



中文翻译:

自噬依赖的游离脂肪酸的生成对于正常的中性粒细胞分化至关重要

中性粒细胞是先天性免疫的关键和短暂的介质,需要不断补充。它们在骨髓中的分化需要大量的细胞质和核重构,但是控制这些耗能的变化的过程尚不清楚。尽管先前的研究表明自噬是分化其他血细胞谱系所必需的,但其在粒细胞生成过程中的功能仍然难以捉摸。在这里,我们已经表明,代谢和自噬是发育程序化的,对于体内中性粒细胞的分化至关重要。缺乏Atg7的中性粒细胞前体具有增加的糖酵解活性,但损害了线粒体的呼吸作用,降低了ATP的产生,并积累了脂质滴。单独抑制自噬介导的脂质降解或脂肪酸氧化足以引起缺陷的分化,而给予线粒体呼吸的脂肪酸或丙酮酸可挽救自噬缺陷的中性粒细胞前体的分化。在一起,我们表明自噬介导的脂解提供了游离脂肪酸,以支持中性粒细胞分化所必需的线粒体呼吸途径。

更新日期:2017-09-12
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