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

• Published in: Nature communications 2014-03, Vol.5 (1), p.3450-3450, Article 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: Article
• Language: English
• Subjects: 14; 14/19; 14/63; 631/250/256; 631/80/86; 692/699/375/380/534; 82; 82/1; 82/29; 82/51; 82/58; Animals; Disease Models, Animal; Humanities and Social Sciences; Inflammation - metabolism; Male; Mice; multidisciplinary; Phosphatidylinositol 3-Kinases - metabolism; Science; Science (multidisciplinary); Stroke - enzymology; Stroke - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2041-1723; 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 (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. PI 3-kinase is a major regulator of inflammatory responses. In this study, the authors show that inhibition of the delta isoform of PI 3-kinase attenuates the release of tumour necrosis factor from microglia as well as the signs and symptoms associated with cerebral stroke in an in vivo mouse model.