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

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

Cite this

Low, P. C., Manzanero, S., Mohannak, N., Narayana, V. K., Nguyen, T. H., Kvaskoff, D., ... Meunier, F. A. (2014). PI3Kdelta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. Nature Communications, 5(3450), 1 - 12. https://doi.org/10.1038/ncomms4450
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, Helena H A ; Broughton, Bradley R S ; Sobey, Christopher G ; Vanhaesebroeck, Bart ; Stow, Jennifer L ; Arumugam, Thiruma ; Meunier, Frederic A. / PI3Kdelta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. In: Nature Communications. 2014 ; Vol. 5, No. 3450. pp. 1 - 12.
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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.",
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Low, PC, Manzanero, S, Mohannak, N, Narayana, VK, Nguyen, TH, Kvaskoff, D, Brennan, FH, Ruitenberg, MJ, Gelderblom, M, Magnus, T, Kim, HHA, Broughton, BRS, Sobey, CG, Vanhaesebroeck, B, Stow, JL, Arumugam, T & Meunier, FA 2014, 'PI3Kdelta inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model' Nature Communications, vol. 5, no. 3450, pp. 1 - 12. https://doi.org/10.1038/ncomms4450

PI3Kdelta 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, Helena H A; Broughton, Bradley R S; Sobey, Christopher G; Vanhaesebroeck, Bart; Stow, Jennifer L; Arumugam, Thiruma; Meunier, Frederic A.

In: Nature Communications, Vol. 5, No. 3450, 2014, p. 1 - 12.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - PI3Kdelta 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, Helena H A

AU - Broughton, Bradley R S

AU - Sobey, Christopher G

AU - Vanhaesebroeck, Bart

AU - Stow, Jennifer L

AU - Arumugam, Thiruma

AU - Meunier, Frederic 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 (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.

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 (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.

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U2 - 10.1038/ncomms4450

DO - 10.1038/ncomms4450

M3 - Article

VL - 5

SP - 1

EP - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 3450

ER -