PI3Kdelta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

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, Helena H A Kim, Bradley R S Broughton, Christopher G Sobey, Bart Vanhaesebroeck, Jennifer L Stow, Thiruma Arumugam, Frederic A Meunier

Research output: Contribution to journalArticleResearchpeer-review

38 Citations (Scopus)

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 (PI3Kdelta) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kdelta 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 PI3Kdelta inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kdelta (p110delta(D910A/D910A)) or wild-type mice pre- or post-treated with the PI3Kdelta inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kdelta as a potential therapeutic target in ischaemic stroke.
Original languageEnglish
Pages (from-to)1 - 12
Number of pages12
JournalNature Communications
Volume5
Issue number3450
DOIs
Publication statusPublished - 2014

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