Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses
Pranvera Sadiku, … , Moira K.B. Whyte, Sarah R. Walmsley
Pranvera Sadiku, … , Moira K.B. Whyte, Sarah R. Walmsley
Published August 14, 2017
Citation Information: J Clin Invest. 2017;127(9):3407-3420. https://doi.org/10.1172/JCI90848.
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Research Article Inflammation Metabolism

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

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.

Authors

Pranvera Sadiku, Joseph A. Willson, Rebecca S. Dickinson, Fiona Murphy, Alison J. Harris, Amy Lewis, David Sammut, Ananda S. Mirchandani, Eilise Ryan, Emily R. Watts, A.A. Roger Thompson, Helen M. Marriott, David H. Dockrell, Cormac T. Taylor, Martin Schneider, Patrick H. Maxwell, Edwin R. Chilvers, Massimilliano Mazzone, Veronica Moral, Chris W. Pugh, Peter J. Ratcliffe, Christopher J. Schofield, Bart Ghesquiere, Peter Carmeliet, Moira K.B. Whyte, Sarah R. Walmsley

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Figure 6

Glycolytic inhibition reverses hypoxic neutrophil survival and persistence in the setting of systemic hypoxia following glycolytic inhibition.

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Glycolytic inhibition reverses hypoxic neutrophil survival and persisten...
(A and B) Apoptosis. Human peripheral blood neutrophils were cultured ex vivo for 20 hours in the presence or absence of dialyzed FBS and glucose-free media (A) or 2DG (B) and apoptosis assessed by morphology. DFBS-glu, dialyzed fetal bovine serum-glucose free media. DFBS-glut, dialyzed fetal bovine serum-glutamine free media. (C–F) In vivo administration of 2DG. WT mice were challenged with nebulized LPS (T0) (3 mg). Six hours after installation (T6), mice were either maintained in normoxia (21% O2) or at 10% O2 over an hour prior to i.p. installation at T10 with 2DG (500 mg/kg) or PBS vehicle control. Mice were sacrificed at 24 hours (T24) and BAL total cell counts (C), neutrophil differential counts (D), neutrophil total counts (E), and neutrophil apoptosis counts (F) performed or lungs harvested, fixed with 10% buffered formalin, paraffin-embedded, and sections stained with H&E (G). Original magnification, ×400. Data represent mean ± SEM, n = 5, with significance determined by one-way ANOVA.