Watts, E. orcid.org/0000-0001-6496-7366, Willison, J., Arienti, S. orcid.org/0000-0002-5406-0012 et al. (18 more authors) (2024) Differential roles for the oxygen sensing enzymes PHD1 and PHD3 in the regulation of neutrophil metabolism and function. Wellcome Open Research, 8. 569. ISSN 2398-502X
Abstract
Background Neutrophils are essential in the early innate immune response to pathogens. Harnessing their antimicrobial powers, without driving excessive and damaging inflammatory responses, represents an attractive therapeutic possibility. The neutrophil population is increasingly recognised to be more diverse and malleable than was previously appreciated. Hypoxic signalling pathways are known to regulate important neutrophil behaviours and, as such, are potential therapeutic targets for regulating neutrophil antimicrobial and inflammatory responses. Methods We used a combination of <ns4:italic>in vivo</ns4:italic> and <ns4:italic>ex vivo</ns4:italic> models, utilising neutrophil and myeloid specific PHD1 or PHD3 deficient mouse lines to investigate the roles of oxygen sensing prolyl hydroxylase enzymes in the regulation of neutrophilic inflammation and immunity. Mass spectrometry and Seahorse metabolic flux assays were used to analyse the role of metabolic shifts in driving the downstream phenotypes. Results We found that PHD1 deficiency drives alterations in neutrophil metabolism and recruitment, in an oxygen dependent fashion. Despite this, PHD1 deficiency did not significantly alter <ns4:italic>ex vivo</ns4:italic> neutrophil phenotypes or <ns4:italic>in vivo</ns4:italic> outcomes in mouse models of inflammation. Conversely, PHD3 deficiency was found to enhance neutrophil antibacterial properties without excessive inflammatory responses. This was not linked to changes in the abundance of core metabolites but was associated with increased oxygen consumption and increased mitochondrial reactive oxygen species (mROS) production. Conclusions PHD3 deficiency drives a favourable neutrophil phenotype in infection and, as such, is an important potential therapeutic target.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 Watts E et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Hypoxia; Inflammation; Neutrophil; PHD1; PHD3; Prolyl hydroxylase |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/K023845/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 Sep 2024 11:25 |
Last Modified: | 23 Sep 2024 11:25 |
Published Version: | http://dx.doi.org/10.12688/wellcomeopenres.19915.2 |
Status: | Published |
Publisher: | F1000 Research Ltd |
Refereed: | Yes |
Identification Number: | 10.12688/wellcomeopenres.19915.2 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:217521 |