Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses
Author(s)
Type
Journal Article
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.
Date Issued
2017-09-01
Date Acceptance
2017-06-29
Citation
Journal of Clinical Investigation, 2017, 127 (9), pp.3413-3426
ISSN
0021-9738
Publisher
American Society for Clinical Investigation
Start Page
3413
End Page
3426
Journal / Book Title
Journal of Clinical Investigation
Volume
127
Issue
9
Copyright Statement
© 2017 Sadiku et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/.
licenses/by/4.0/.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000408842300022&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
HYPOXIA-INDUCIBLE-FACTOR
PYRUVATE-KINASE M2
DOMAIN PROTEIN-2
PHD2 MUTATION
HIF-1-ALPHA
HIF
MICE
ERYTHROCYTOSIS
SURVIVAL
INFLAMMATION
Publication Status
Published
Date Publish Online
2017-08-14