Investigating the metabolic plasticity of inflammatory neutrophils during infection
dc.contributor.advisor
Rossi, Adriano
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Walmsley, Sarah
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Campbell, Colin
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Arienti, Simone
dc.contributor.sponsor
Medical Research Foundation
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dc.date.accessioned
2023-01-27T14:43:30Z
dc.date.available
2023-01-27T14:43:30Z
dc.date.issued
2023-01-27
dc.description.abstract
Neutrophils are required to function and survive under challenging conditions characterised by tissue hypoxia and nutrient scarcity. Neutrophils are well suited to rapidly respond to infection and engage with metabolic pathways for the rapid generation of substrates used to meet their energy demands, reactive oxygen species (ROS) production, and delaying constitutive apoptosis programmes. By using a variety of assays, I investigated the dynamic metabolic adaptations of infected neutrophils exposed to both hypoxia and glucose depletion. I observed that glucose depletion reduces apoptosis of infected neutrophils, and that hypoxia further promotes neutrophil phagocytosis. Mass spectrometry metabolite quantification and metabolic flux analysis revealed that neutrophils upregulate the pentose phosphate pathway to sustain ROS production and bacterial killing. Gluconeogenesis, glycogenolysis and the glycerol 3-phosphate pathways are all critical for neutrophil bacterial control and hypoxic adaptation. Finally, investigation of PHD3-/- neutrophils revealed a phenotype of improved bacterial control and reduced inflammation which might have beneficial therapeutic implication.
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dc.identifier.uri
https://hdl.handle.net/1842/39777
dc.identifier.uri
http://dx.doi.org/10.7488/era/3025
dc.language.iso
en
en
dc.publisher
The University of Edinburgh
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dc.relation.hasversion
Sadiku P, Willson JA, et al. - Neutrophils Fuel Effective Immune Responses through Gluconeogenesis and Glycogenesis. Cell Metab. 2021 Feb 2;33(2):411-423.e4. doi: 10.1016/j.cmet.2020.11.016. Epub 2020 Dec 10. Cell Metab. 2021 May 4;33(5):1062-1064. PMID: 33306983; PMCID: PMC7863914.
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dc.relation.hasversion
Willson JA, Arienti S et al. - Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle. Blood. 2022 Jan 13;139(2):281-286. doi: 10.1182/blood.2021011010. PMID: 34411229; PMCID: PMC8832465.
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dc.subject
Inflammatory Neutrophils
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Metabolic Plasticity
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dc.subject
reactive oxygen species
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ROS
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infected neutrophils
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dc.subject
hypoxia
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glucose depletion
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neutrophil phagocytosis
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dc.title
Investigating the metabolic plasticity of inflammatory neutrophils during infection
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dc.type
Thesis or Dissertation
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dc.type.qualificationlevel
Doctoral
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dc.type.qualificationname
PhD Doctor of Philosophy
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