Autophagy-Dependent Generation of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation

Abstract

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. Rapid neutrophil differentiation is key to the immune response against invading bacteria. Here, Riffelmacher et al. show that autophagy, the main recycling process in the cell, provides energy for neutrophil differentiation by degrading lipid droplets. This opens possible novel therapeutic avenues for the differentiation treatment of granulocytic leukemia.