title: PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model.
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.
authors.affiliation: 1] Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia [2].
authors.forename: Pei Ching
authors.initials: PC
authors.lastname: Low
authors.affiliation: 1] School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia [2].
authors.forename: Silvia
authors.initials: S
authors.lastname: Manzanero
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Nika
authors.initials: N
authors.lastname: Mohannak
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Narayana
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Tam H
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Kvaskoff
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Faith H
authors.initials: FH
authors.lastname: Brennan
authors.affiliation: 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.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Ruitenberg
authors.affiliation: Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Gelderblom
authors.affiliation: Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Kim
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Brad R S
authors.initials: BR
authors.lastname: Broughton
authors.affiliation: Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.affiliation: UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street London WC1E 6DD, UK.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
authors.affiliation: 1] School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia [2].
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Frédéric A
authors.initials: FA
authors.lastname: Meunier
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D020521:Stroke / Q000201:enzymology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D014409:Tumor Necrosis Factor-alpha; C421683:Pik3cd protein, mouse