Differential roles for the oxygen sensing enzymes PHD1 and PHD3 in the regulation of neutrophil metabolism and function

Watts, Emily and Willison, Joseph and Arienti, Simone and Sadiku, Pranvera and Coelho, Patricia and Sanchez-Garcia, Manuel and Zhang, Ailiang and Murphy, Fiona and Dickinson, Rebecca and Mirchandani, Ananda and Morrison, Tyler and Lewis, Amy and Vermaelen, Wesley and Ghesquiere, Bart and Carmeliet, Peter and Mazzone, Massimilliano and Maxwell, Patrick and Pugh, Christopher and Dockrell, David and Whyte, Moira and Walmsley, Sarah (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 (https://doi.org/10.12688/wellcomeopenres.19915.2)

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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 in vivo and ex vivo 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 ex vivo neutrophil phenotypes or in vivo 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.

ORCID iDs

Watts, Emily, Willison, Joseph, Arienti, Simone, Sadiku, Pranvera, Coelho, Patricia, Sanchez-Garcia, Manuel, Zhang, Ailiang, Murphy, Fiona ORCID logoORCID: https://orcid.org/0000-0001-7925-0632, Dickinson, Rebecca, Mirchandani, Ananda, Morrison, Tyler, Lewis, Amy, Vermaelen, Wesley, Ghesquiere, Bart, Carmeliet, Peter, Mazzone, Massimilliano, Maxwell, Patrick, Pugh, Christopher, Dockrell, David, Whyte, Moira and Walmsley, Sarah;
CORE (COnnecting REpositories)