Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism

Watts, Emily R. and Howden, Andrew J.M. and Morrison, Tyler and Sadiku, Pranvera and Hukelmann, Jens and von Kriegsheim, Alex and Ghesquiere, Bart and Murphy, Fiona and Mirchandani, Ananda S. and Humphries, Duncan C. and Grecian, Robert and Ryan, Eilise M. and Coelho, Patricia and Blanco, Gio Rodriguez and Plant, Tracie M. and Dickinson, Rebecca S. and Finch, Andy and Vermaelen, Wesley and Cantrell, Doreen A. and Whyte, Moira K. and Walmsley, Sarah R. (2021) Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism. Journal of Clinical Investigation, 131 (10). e134073. ISSN 0021-9738 (https://doi.org/10.1172/JCI134073)

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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.

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