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

Sadiku, Pranvera and Willson, Joseph A. and Dickinson, Rebecca S. and Murphy, Fiona and Harris, Alison J. and Lewis, Amy and Sammut, David and Mirchandani, Ananda S. and Ryan, Eilise and Watts, Emily R. and Thompson, A.A.Roger and Marriott, Helen M. and Dockrell, David H. and Taylor, Cormac T. and Schneider, Martin and Maxwell, Patrick H. and Chilvers, Edwin R. and Mazzone, Massimilliano and Moral, Veronica and Pugh, Chris W. and Ratcliffe, Peter J. and Schofield, Christopher J. and Ghesquiere, Bart and Carmeliet, Peter and Whyte, Moira K.B. and Walmsley, Sarah R. (2017) Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses. Journal of Clinical Investigation, 127 (9). pp. 3407-3420. ISSN 0021-9738 (https://doi.org/10.1172/JCI90848)

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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.

ORCID iDs

Sadiku, Pranvera, Willson, Joseph A., Dickinson, Rebecca S., Murphy, Fiona ORCID logoORCID: https://orcid.org/0000-0001-7925-0632, Harris, Alison J., Lewis, Amy, Sammut, David, Mirchandani, Ananda S., Ryan, Eilise, Watts, Emily R., Thompson, A.A.Roger, Marriott, Helen M., Dockrell, David H., Taylor, Cormac T., Schneider, Martin, Maxwell, Patrick H., Chilvers, Edwin R., Mazzone, Massimilliano, Moral, Veronica, Pugh, Chris W., Ratcliffe, Peter J., Schofield, Christopher J., Ghesquiere, Bart, Carmeliet, Peter, Whyte, Moira K.B. and Walmsley, Sarah R.;
CORE (COnnecting REpositories)