Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 55, Issue -, Pages 236-248Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2015.12.016
Keywords
Ischemia; Microglia; Hippo/MST1; Src; I kappa B
Categories
Funding
- National Science Foundation of China [81125010, 81030025]
- National Basic Research Program of China (973) [2012CB910701, 2013DFA31990]
- Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation from Chinese Academy of Sciences
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Cerebral ischemia-reperfusion injury is a major public health concern that causes high rates of disability and mortality in adults. Microglial activation plays a crucial role in ischemic stroke-induced alteration of the immune microenvironment. However, the mechanism underlying the triggering of microglial activation by ischemic stroke remains to be elucidated. Previously, we demonstrated that the protein kinase Hippo/MST1 plays an important role in oxidative stress-induced cell death in mammalian primary neurons and that the protein kinase c-Abl phosphorylates MST1 at Y433, which increases MST1 kinase activity. Microglial activation has been implicated as a secondary detrimental cellular response that contributes to neuronal cell death in ischemic stroke. Here, we are the first, to our knowledge, to demonstrate that MST1 mediates stroke-induced microglial activation by directly phosphorylating I kappa B alpha at residues S32 and S36. We further demonstrate that Src kinase functions upstream of MST1-I kappa B signaling during microglial activation. Specific deletion of MST1 in microglia mitigates stroke-induced brain injury. Therefore, we propose that Src-MST1-I kappa B signaling plays a critical role in stroke-induced microglial activation. Together with our previous work demonstrating that MST1 is important for oxidative stress-induced neuronal cell death, our results indicate that MST1 could represent a potent therapeutic target for ischemic stroke. (C) 2015 Elsevier Inc. All rights reserved.
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