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J Clin Invest. 2017 Sep 1;127(9):3407-3420. doi: 10.1172/JCI90848. Epub 2017 Aug 14.

Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses.

Author information

1
MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
2
Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium.
3
Academic Unit of Respiratory Medicine and.
4
Academic Unit of Immunology and Infectious Diseases, Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom.
5
UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin, Ireland.
6
General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
7
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
8
Laboratory of Tumour Inflammation and Angiogenesis, Department of Oncology, Leuven, Belgium.
9
Nuffield Department of Medicine and.
10
The Department of Chemistry, University of Oxford, Oxford, United Kingdom.

Abstract

Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival. These enhanced neutrophil responses were dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF-prolyl hydroxylase inhibitor replicated the Phd2-deficient phenotype of delayed inflammation resolution. Together, these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils under normoxic conditions and link intrinsic regulation of glycolysis and glycogen stores to the resolution of neutrophil-mediated inflammatory responses. These results demonstrate the therapeutic potential of targeting metabolic pathways in the treatment of inflammatory disease.

PMID:
28805660
PMCID:
PMC5669581
DOI:
10.1172/JCI90848
[Indexed for MEDLINE]
Free PMC Article

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