PI3K[delta] inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

• Published in: Nature communications Vol. 5; p. 3450
• Main Authors: Low, Pei Ching, Manzanero, Silvia, Mohannak, Nika, Narayana, Vinod K, Nguyen, Tam H, Kvaskoff, David, Brennan, Faith H, Ruitenberg, Marc J, Gelderblom, Mathias, Magnus, Tim, Kim, Hyun Ah, Broughton, Brad R S, Sobey, Christopher G, Vanhaesebroeck, Bart, Stow, Jennifer L, Arumugam, Thiruma V, Meunier, Frédéric A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.03.2014
• ISSN: 2041-1723
• DOI: 10.1038/ncomms4450

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.