Investigating the metabolic plasticity of inflammatory neutrophils during infection

Abstract

Neutrophils are required to function and survive under challenging conditions characterised by tissue hypoxia and nutrient scarcity. Neutrophils are well suited to rapidly respond to infection and engage with metabolic pathways for the rapid generation of substrates used to meet their energy demands, reactive oxygen species (ROS) production, and delaying constitutive apoptosis programmes. By using a variety of assays, I investigated the dynamic metabolic adaptations of infected neutrophils exposed to both hypoxia and glucose depletion. I observed that glucose depletion reduces apoptosis of infected neutrophils, and that hypoxia further promotes neutrophil phagocytosis. Mass spectrometry metabolite quantification and metabolic flux analysis revealed that neutrophils upregulate the pentose phosphate pathway to sustain ROS production and bacterial killing. Gluconeogenesis, glycogenolysis and the glycerol 3-phosphate pathways are all critical for neutrophil bacterial control and hypoxic adaptation. Finally, investigation of PHD3-/- neutrophils revealed a phenotype of improved bacterial control and reduced inflammation which might have beneficial therapeutic implication.