PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model — ASN Events
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  3. PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model (#119)

Pei Ching (Regine) Low 1 2 , Silvia Manzanero 2 , Vinod K Narayana 2 , Tam H Nguyen 2 , David Kvaskoff 2 , Faith H Brennan 2 , Marc J Ruitenberg 2 , Mathias Gelderblom 3 , Tim Magnus 3 , Hyun Ah Kim 4 , Brad RS Broughton 4 , Christopher G Sobey 4 , Bart Vanhaesebroeck 1 , Jennifer L Stow 2 , Thiruma V Arumugam 5 , Frédéric A Meunier 2
  1. UCL Cancer Institute, London, UK, United Kingdom
  2. The University of Queensland, Brisbane, Queensland, Australia
  3. Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  4. Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia
  5. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

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 ischemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumor necrosis factor alpha (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kd) controls intracellular TNF trafficking in macrophages1 and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kd inhibition confers protection in ischemia/reperfusion (I/R) 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 PI3Kd inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kd (p110dD910A/D910A) or wild-type mice pre- or post-treated with the PI3Kd inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kd as a potential therapeutic target in ischemic stroke2.

  1. Low P.C., Misaki R., Schroder K., Stanley A.C., Sweet M.J., Teasdale R.D., Vanhaesebroeck B., Meunier F.A., Taguchi T., and Stow J.L. (2010). Phosphoinositide 3-kinase δ regulates membrane fission of Golgi carriers for selective cytokine secretion. Journal of Cell Biology 190: 1053-1065.
  2. Low P.C., Manzanero S., Mohannak N., Narayana V.K., Nguyen T.H., Kvaskoff D., Brennan F.H., Ruitenberg M.J., Gelderblom M., Magnus T., Kim H.A., Broughton B.R., Sobey C.G., Vanhaesebroeck B., Stow J.L., Arumugam T.V. and Meunier F.A. (2014) PI3Kd inhibitor reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. Nature Communications Mar14; 5, 3450.