PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

Pei Ching Low, Silvia Manzanero, Nika Mohannak, Vinod K. Narayana, Tam H. Nguyen, David Kvaskoff, Faith H. Brennan, Marc J. Ruitenberg, Mathias Gelderblom, Tim Magnus, Hyun Ah Kim, Brad R. S. Broughton, Christopher G. Sobey, Bart Vanhaesebroeck, Jennifer L. Stow, Thiruma V. Arumugam () and Frédéric A. Meunier ()
Additional contact information
Pei Ching Low: Queensland Brain Institute, The University of Queensland
Silvia Manzanero: School of Biomedical Sciences, The University of Queensland
Nika Mohannak: Queensland Brain Institute, The University of Queensland
Vinod K. Narayana: Queensland Brain Institute, The University of Queensland
Tam H. Nguyen: Queensland Brain Institute, The University of Queensland
David Kvaskoff: Queensland Brain Institute, The University of Queensland
Faith H. Brennan: School of Biomedical Sciences, The University of Queensland
Marc J. Ruitenberg: Queensland Brain Institute, The University of Queensland
Mathias Gelderblom: University Medical Center Hamburg-Eppendorf
Tim Magnus: University Medical Center Hamburg-Eppendorf
Hyun Ah Kim: Vascular Biology and Immunopharmacology Group, Monash University
Brad R. S. Broughton: Vascular Biology and Immunopharmacology Group, Monash University
Christopher G. Sobey: Vascular Biology and Immunopharmacology Group, Monash University
Bart Vanhaesebroeck: UCL Cancer Institute, Paul O'Gorman Building, University College London
Jennifer L. Stow: Institute for Molecular Bioscience, The University of Queensland
Thiruma V. Arumugam: School of Biomedical Sciences, The University of Queensland
Frédéric A. Meunier: Queensland Brain Institute, The University of Queensland

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kδ) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kδ inhibition confers protection in ischaemia/reperfusion models of stroke. In vitro, restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia—an effect that is sensitive to PI3Kδ inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kδ (p110δD910A/D910A) or wild-type mice pre- or post-treated with the PI3Kδ inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kδ as a potential therapeutic target in ischaemic stroke.

Date: 2014
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DOI: 10.1038/ncomms4450

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