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: 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 S Broughton, Christopher G Sobey, Bart Vanhaesebroeck, Jennifer L Stow, Thiruma V Arumugam, Frédéric A Meunier
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 3450 (Mar 14 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 24625684 (Publication Type: Journal Article)

Chemical References

• Tumor Necrosis Factor-alpha
• Class I Phosphatidylinositol 3-Kinases
• Pik3cd protein, mouse

Topics

• Animals
• Class I Phosphatidylinositol 3-Kinases
• Disease Models, Animal
• Inflammation (metabolism)
• Male
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Stroke (enzymology, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)