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Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism
Emily R. Watts, … , Moira K. Whyte, Sarah R. Walmsley
Emily R. Watts, … , Moira K. Whyte, Sarah R. Walmsley
Published April 6, 2021
Citation Information: J Clin Invest. 2021;131(10):e134073. https://doi.org/10.1172/JCI134073.
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Research Article Inflammation Metabolism Article has an altmetric score of 3

Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism

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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.

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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Figure 8

Hypoxia promotes a hyperinflammatory neutrophil phenotype abrogated by lysosomal inhibition.

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Hypoxia promotes a hyperinflammatory neutrophil phenotype abrogated by l...
(A) Body temperature of mice housed in hypoxia (10% O2) or normoxia for 24 hours after nebulized LPS and untreated mice housed in hypoxia; n = 4 over 2 experiments, analyzed by 2-way ANOVA with Tukey’s multiple comparisons test. **P < 0.01, ****P < 0.0001. BAL supernatant from normoxic and hypoxic mice 24 hours after LPS was analyzed for (B) albumin (n = 9 over 2 experiments) and (C) IgM (n = 5 over one experiment) by ELISA. (D) BAL neutrophil counts from normoxic or hypoxic mice following nebulized LPS; n = 4 (one experiment) at 2 hour and 48 hour time points, or n = 8 (2 experiments) at 6 hour and 24 hour time points. Significance analyzed by multiple t tests (corrected for multiple comparisons using Bonferroni method). (E) Lung neutrophil counts (n = 6 over 2 experiments) and (F) blood neutrophil counts (n = 9 over 3 experiments) of mice housed in normoxia or hypoxia for 24 hours following LPS nebulization. BAL neutrophils isolated 24 hours after nebulized LPS from normoxic or hypoxic mice were analyzed by flow cytometry for expression of (G) CD11b and (H) CD62L (n = 6–7 over 2 experiments). (I) Body temperatures and (J) BAL neutrophil counts from mice 24 hours after LPS nebulization, treated with i.p. chloroquine or i.p. PBS at 4 hours and housed in normoxia or hypoxia. (K) BAL neutrophils incubated ex vivo with DQ-Green BSA and analyzed by flow cytometry and (L) elastase activity in BAL supernatant from the same mice. I, K, and L: n = 9–10 over 3 experiments. J: n = 6–7 over 2 experiments. J–L used unpaired t test. I used Mann-Whitney test of significance (data not normally distributed). In A and D, data represent mean ± SEM. Data in B, C, and E–L represent individual values and mean ± SEM.

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