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Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice

Walmsley, S. R., Chilvers, E. R., Thompson, A. A., Vaughan, K., Marriott, H. M., Parker, L. C., Shaw, G., Parmar, S., Schneider, M., Sabroe, I., Dockrell, D. H., Milo, M., Taylor, C. T., Johnson, R. S., Pugh, C. W., Ratcliffe, P. J., Maxwell, P. H., Carmeliet, P. and Whyte, M. K. B. (2011) Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. The Journal of clinical investigation, 121 (3). pp. 1053-63. ISSN 1558-8238

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Abstract

The regulation of neutrophil lifespan by induction of apoptosis is critical for maintaining an effective host response and preventing excessive inflammation. The hypoxia-inducible factor (HIF) oxygen-sensing pathway has a major effect on the susceptibility of neutrophils to apoptosis, with a marked delay in cell death observed under hypoxic conditions. HIF expression and transcriptional activity are regulated by the oxygen-sensitive prolyl hydroxylases (PHD1-3), but the role of PHDs in neutrophil survival is unclear. We examined PHD expression in human neutrophils and found that PHD3 was strongly induced in response to hypoxia and inflammatory stimuli in vitro and in vivo. Using neutrophils from mice deficient in Phd3, we demonstrated a unique role for Phd3 in prolonging neutrophil survival during hypoxia, distinct from other hypoxia-associated changes in neutrophil function and metabolic activity. Moreover, this selective defect in neutrophil survival occurred in the presence of preserved HIF transcriptional activity but was associated with upregulation of the proapoptotic mediator Siva1 and loss of its binding target Bcl-xL. In vivo, using an acute lung injury model, we observed increased levels of neutrophil apoptosis and clearance in Phd3-deficient mice compared with WT controls. We also observed reduced neutrophilic inflammation in an acute mouse model of colitis. These data support what we believe to be a novel function for PHD3 in regulating neutrophil survival in hypoxia and may enable the development of new therapeutics for inflammatory disease.

Item Type: Article
Copyright, Publisher and Additional Information: © 2011 American Society for Clinical Investigation. Reproduced in accordance with the publisher's self-archiving policy.
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 29 Mar 2012 09:40
Last Modified: 20 Jun 2014 17:34
Published Version: http://dx.doi.org/10.1172/JCI43273
Status: Published
Publisher: American Society for Clinical Investigation
Identification Number: 10.1172/JCI43273
Related URLs:
URI: http://eprints.whiterose.ac.uk/id/eprint/43792

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