Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism
Emily Watts, Andrew J.M. Howden, Tyler Morrison, Pranvera Sadiku, Jens Hukelmann, Alex von Kriegsheim, Bart Ghesquière, Fiona Murphy, Ananda S. Mirchandani, Duncan C. Humphries, Robert Grecian, Eilíse M. Ryan, Patrícia Coelho, Giovanny Rodriguez Blanco, Tracie Plant, Rebecca Dickinson, Andy Finch, Wesley Vermaelen, Doreen A. Cantrell, Moira K. B. Whyte, Sarah R. Walmsley
Abstract
Limiting dysfunctional neutrophilic inflammation while preserving effective immunity requires a better understanding of the processes that dictate neutrophil function in the tissues. Quantitative mass-spectrometry identified how inflammatory murine neutrophils regulated expression of cell surface receptors, signal transduction networks, and metabolic machinery to shape neutrophil phenotypes in response to hypoxia. Through the tracing of labeled amino acids into metabolic enzymes, proinflammatory mediators, and granule proteins, we demonstrated that ongoing protein synthesis shapes the neutrophil proteome. To maintain energy supplies in the tissues, neutrophils consumed extracellular proteins to fuel central carbon metabolism. The physiological stresses of hypoxia and hypoglycemia, characteristic of inflamed tissues, promoted this extracellular protein scavenging with activation of the lysosomal compartment, further driving exploitation of the protein-rich inflammatory milieu. This study provides a comprehensive map of neutrophil proteomes, analysis of which has led to the identification of active catabolic and anabolic pathways that enable neutrophils to sustain synthetic and effector functions in the tissues.