Riffelmacher Thomas, Clarke Alexander, Richter Felix C, Stranks Amanda, Pandey Sumeet, Danielli Sara, Hublitz Philip, Yu Zhanru, Johnson Errin, Schwerd Tobias, McCullagh James, Uhlig Holm, Jacobsen Sten Eirik W, Simon Anna Katharina
Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
Immunity. 2017 Sep 19;47(3):466-480.e5. doi: 10.1016/j.immuni.2017.08.005. Epub 2017 Sep 12.
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.
中性粒细胞是先天性免疫的关键且寿命短暂的介质，需要持续补充。它们在骨髓中的分化需要广泛的细胞质和细胞核重塑，但控制这些耗能变化的过程尚不清楚。虽然先前的研究表明自噬是其他血细胞谱系分化所必需的，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，代谢和自噬在体内是由发育程序控制的，并且对中性粒细胞的分化至关重要。Atg7缺陷的中性粒细胞前体具有增加的糖酵解活性，但线粒体呼吸受损，ATP产生减少，并积累脂滴。单独抑制自噬介导的脂质降解或脂肪酸氧化足以导致分化缺陷，而给予脂肪酸或丙酮酸用于线粒体呼吸可挽救自噬缺陷的中性粒细胞前体的分化。我们共同表明，自噬介导的脂解提供游离脂肪酸，以支持对中性粒细胞分化至关重要的线粒体呼吸途径。
