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

Autor:	Sadiku P; MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium., Willson JA; MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Dickinson RS; MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Murphy F; MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Harris AJ; MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Lewis A; Academic Unit of Respiratory Medicine and., Sammut D; Academic Unit of Respiratory Medicine and., Mirchandani AS; MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Ryan E; MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Watts ER; MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Thompson AAR; Academic Unit of Respiratory Medicine and., Marriott HM; Academic Unit of Immunology and Infectious Diseases, Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom., Dockrell DH; Academic Unit of Immunology and Infectious Diseases, Department of Infection, Immunity and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom., Taylor CT; UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin, Ireland., Schneider M; General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany., Maxwell PH; Department of Medicine, University of Cambridge, Cambridge, United Kingdom., Chilvers ER; Department of Medicine, University of Cambridge, Cambridge, United Kingdom., Mazzone M; Laboratory of Tumour Inflammation and Angiogenesis, Department of Oncology, Leuven, Belgium., Moral V; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium., Pugh CW; Nuffield Department of Medicine and., Ratcliffe PJ; Nuffield Department of Medicine and., Schofield CJ; The Department of Chemistry, University of Oxford, Oxford, United Kingdom., Ghesquiere B; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium., Carmeliet P; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium., Whyte MK; MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom., Walmsley SR; MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2017 Sep 01; Vol. 127 (9), pp. 3407-3420. Date of Electronic Publication: 2017 Aug 14.
DOI:	10.1172/JCI90848
Abstrakt:	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.
Databáze:	MEDLINE
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