PI3K delta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model Academic Article uri icon

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

  • Low, PC
  • Manzanero, S
  • Mohannak, N
  • Narayana, VK
  • Nguyen, TH
  • Kvaskoff, D
  • Brennan, FH
  • Ruitenberg, MJ
  • Gelderblom, M
  • Magnus, T
  • Kim, HA
  • Broughton, BRS
  • Sobey, CG
  • Vanhaesebroeck, B
  • Stow, JL
  • Arumugam, TV
  • Meunier, FA

publication date

  • 2014