Abstract
SummaryNeutrophils 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.
Highlights
Neutrophils are the most abundant and short-lived human immune cells and are rapidly recruited to sites of infection as a first line of defense
We show that autophagy-mediated lipid breakdown provides free fatty acids (FFAs) to support the fatty acid oxidation (FAO)-OXPHOS pathway for ATP production, which is essential for neutrophil differentiation
We found robust autophagic flux at the myeloblast cells (MBs) and MBs proceed through promyelocyte (MC) stages, which decreased at the MM and band cell (BC) stages and slightly increased again in mature polymorphonuclear neutrophil (PMN) (Figure 1D)
Summary
Neutrophils are the most abundant and short-lived human immune cells and are rapidly recruited to sites of infection as a first line of defense. They have attracted new attention with unexpected findings on their heterogeneity and plasticity (Nauseef and Borregaard, 2014) and their ability to survive long term and shape adaptive immune responses (Nicolas-Avila et al, 2017). MBs proceed through promyelocyte (MC), metamyelocyte (MM), and band cell (BC) stages to become a mature polymorphonuclear neutrophil (PMN) (Bardoel et al, 2014) This process is characterized by striking remodeling of the nucleus and temporally regulated granule generation by timed synthesis, which clearly demarcates stages of differentiation
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