PI3K delta 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, Hyun Ah Kim, Brad RS Broughton, Christopher G Sobey, Bart Vanhaesebroeck, Jennifer L Stow, Thiruma V Arumugam, Frederic A Meunier
Nature Communications | NATURE PUBLISHING GROUP | Published : 2014
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 ..View full abstract
Awarded by National Health and Medical Research Council of Australia (NHMRC)
We thank members of the Meunier and Arumugam laboratories for technical assistance, Geoffrey Osborne for his expertise support in flow cytometry, Rowan Tweedale for critical appraisal of this article and Shaun Jackson (Melbourne University) for the initial gift of IC87114. We also thank technical staff of The University of Queensland Biological Resources and Queensland Brain Institute animal facility for maintaining the mice (PI3Kd transgenic and wild type) used in this study. The work was supported by a National Health and Medical Research Council of Australia (NHMRC) project Grant 1005964 (to F. A. M. and T. V. A.). M.J.R. is supported by a Career Development Fellowship from SpinalCure Australia, F. A. M. is a Senior Research Fellow of the NHMRC and T. V. A. was a Future Fellow of the Australian Research Council.