PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model
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PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. / 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.
In: NAT COMMUN, Vol. 5, 2014, p. 3450.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model
AU - Low, Pei Ching
AU - Manzanero, Silvia
AU - Mohannak, Nika
AU - Narayana, Vinod K
AU - Nguyen, Tam H
AU - Kvaskoff, David
AU - Brennan, Faith H
AU - Ruitenberg, Marc J
AU - Gelderblom, Mathias
AU - Magnus, Tim
AU - Kim, Hyun Ah
AU - Broughton, Brad R S
AU - Sobey, Christopher G
AU - Vanhaesebroeck, Bart
AU - Stow, Jennifer L
AU - Arumugam, Thiruma V
AU - Meunier, Frédéric A
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
U2 - 10.1038/ncomms4450
DO - 10.1038/ncomms4450
M3 - SCORING: Journal article
C2 - 24625684
VL - 5
SP - 3450
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
ER -