Advertisement

ResearchIn-Press PreviewInflammationMetabolism Free access | 10.1172/JCI134073

Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism

Emily R. Watts,1 Andrew J.M. Howden,2 Tyler Morrison,1 Pranvera Sadiku,1 Jens L. Hukelmann,2 Alex von Kriegsheim,3 Bart Ghesquière,4 Fiona Murphy,1 Ananda S. Mirchandani,1 Duncan C. Humphries,1 Robert Grecian,1 Eilise M. Ryan,1 Patricia Coelho,1 Giovanny Rodriguez-Blanco,3 Tracie M. Plant,1 Rebecca S. Dickinson,1 Andrew J. Finch,3 Wesley Vermaelen,4 Doreen A. Cantrell,2 Moira K.B. Whyte,1 and Sarah R. Walmsley1

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Watts, E. in: JCI | PubMed | Google Scholar |

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Howden, A. in: JCI | PubMed | Google Scholar

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Morrison, T. in: JCI | PubMed | Google Scholar |

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Sadiku, P. in: JCI | PubMed | Google Scholar

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Hukelmann, J. in: JCI | PubMed | Google Scholar |

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by von Kriegsheim, A. in: JCI | PubMed | Google Scholar |

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Ghesquière, B. in: JCI | PubMed | Google Scholar

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Murphy, F. in: JCI | PubMed | Google Scholar

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Mirchandani, A. in: JCI | PubMed | Google Scholar

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Humphries, D. in: JCI | PubMed | Google Scholar |

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Grecian, R. in: JCI | PubMed | Google Scholar |

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Ryan, E. in: JCI | PubMed | Google Scholar

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Coelho, P. in: JCI | PubMed | Google Scholar |

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Rodriguez-Blanco, G. in: JCI | PubMed | Google Scholar |

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Plant, T. in: JCI | PubMed | Google Scholar

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Dickinson, R. in: JCI | PubMed | Google Scholar

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Finch, A. in: JCI | PubMed | Google Scholar |

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Vermaelen, W. in: JCI | PubMed | Google Scholar

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Cantrell, D. in: JCI | PubMed | Google Scholar

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Whyte, M. in: JCI | PubMed | Google Scholar |

1Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom

2Division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom

3Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom

4Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Centre, Leuven, Belgium

Find articles by Walmsley, S. in: JCI | PubMed | Google Scholar |

Published April 6, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI134073.
Copyright © 2021, American Society for Clinical Investigation
Published April 6, 2021 - Version history
View PDF
Abstract

Limiting dysfunctional neutrophilic inflammation whilst 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 labelled amino acids into metabolic enzymes, pro-inflammatory 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 hypoglycaemia, characteristic of inflamed tissues, promoted this extra-cellular 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 which enable neutrophils to sustain synthetic and effector functions in the tissues.

Graphical Abstract
graphical abstract
Supplemental material

View Figure S1

View Figure S2

View Figure S3

View Figure S4

View Figure S5

View Table S5

Version history
  • Version 1 (April 6, 2021): In-Press Preview
Advertisement
Advertisement