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

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 (PI3K delta) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3K delta 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 PI3Kd inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3K delta (p110 delta(D910A/ D910A)) or wild-type mice pre- or post-treated with the PI3K delta inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3K delta as a potential therapeutic target in ischaemic stroke.