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 September 1, 2017; First 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 1

Myeloid-specific Phd2 deficiency results in aberrant neutrophilic inflammation.

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Myeloid-specific Phd2 deficiency results in aberrant neutrophilic inflam...
WT (white bars) and myeloid-specific Phd2–/– (black bars) mice were studied in parallel. (A–E) Mice were infected via the trachea with 1 × 107 CFU of TIGR4. Cells were harvested by BAL at 14 hours and total cell counts (A) and neutrophil differential counts (B) obtained. Total IgM release into bronchoalveolar fluid (C) and viable bacterial counts recovered from homogenized lung (D) or whole blood (E) were performed in parallel (n = 15). (F–L) Acute lung injury. Intratracheal LPS (0.3 mg) was instilled in anesthetized mice. Mice were sacrificed at 6 hours after challenge and cells harvested by BAL for total cell counts (F) and surface expression of CXCR2 (G) and CDlla (H). At 24 (I), 48, and 72 hours (J–N) after challenge, cells/supernatants were harvested by BAL for total cell counts (I, J, L), neutrophil differential counts (I, K, L), morphological counts of apoptosis (M), and measures of total IgM release (N) (n = 7). (O) DSS colitis. Six days following DSS diet–induced colitis, colonic sections were harvested, paraffin-fixed, and anti-MPO antibody stained. ALI, acute lung injury. P values obtained via unpaired t test.