Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1172/jci90848

Type

Journal article

Journal

The Journal of clinical investigation

Publication Date

09/2017

Volume

127

Pages

3407 - 3420

Addresses

Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium.

Keywords

Leukocytes, Neutrophils, Animals, Mice, Inbred C57BL, Humans, Mice, Pneumococcal Infections, Colitis, Acute Disease, Inflammation, Glycogen, Bronchoalveolar Lavage, Signal Transduction, Glycolysis, Phenotype, Immunity, Innate, Lung Injury, Hypoxia-Inducible Factor-Proline Dioxygenases