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

  • Nat Commun. 2014 Mar 14;5:3450. doi: 10.1038/ncomms4450.
Pei Ching Low  1 ,  Silvia Manzanero  2 ,  Nika Mohannak  3 ,  Vinod K Narayana  3 ,  Tam H Nguyen  3 ,  David Kvaskoff  3 ,  Faith H Brennan  4 ,  Marc J Ruitenberg  5 ,  Mathias Gelderblom  6 ,  Tim Magnus  6 ,  Hyun Ah Kim  7 ,  Brad R S Broughton  7 ,  Christopher G Sobey  7 ,  Bart Vanhaesebroeck  8 ,  Jennifer L Stow  9 ,  Thiruma V Arumugam  2 ,  Frédéric A Meunier  3
Affiliations
  • 1. 1] Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia [2].
  • 2. 1] School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia [2].
  • 3. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 4. School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 5. 1] Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia [2] School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
  • 6. Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 7. Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
  • 8. UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London WC1E 6DD, UK.
  • 9. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
PMID: 24625684 DOI: 10.1038/ncomms4450
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 (p110δ(D910A/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.

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