IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v5y2014i1d10.1038_ncomms4450.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    School of Biomedical Sciences, 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
    Present address: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 117597, Singapore)

  • Frédéric A. Meunier

    (Queensland Brain Institute, The University of Queensland)

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.

Suggested Citation

  • 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. , 2014. "PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4450
    DOI: 10.1038/ncomms4450
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms4450
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms4450?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4450. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.