Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism |
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Authors: | Emily R. Watts Andrew J.M. Howden Tyler Morrison Pranvera Sadiku Jens Hukelmann Alex von Kriegsheim Bart Ghesquiere Fiona Murphy Ananda S. Mirchandani Duncan C. Humphries Robert Grecian Eilise M. Ryan Patricia Coelho Gio Rodriguez Blanco Tracie M. Plant Rebecca S. Dickinson Andy Finch Wesley Vermaelen Doreen A. Cantrell Moira K. Whyte Sarah R. Walmsley |
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Affiliation: | 1.University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.;2.Division of Cell Signaling and Immunology, University of Dundee, Dundee, United Kingdom.;3. Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, United Kingdom.;4.Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium. |
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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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Keywords: | Inflammation Metabolism |
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