Hippo/MST1 signaling mediates microglial activation following acute cerebral ischemia–reperfusion injury

Siqi Zhao, Jie Yin, Lujun Zhou, Feng Yan, Qing He, Li Huang, Shengyi Peng, Junying Jia, Jinbo Cheng, Hong Chen, Wufan Tao, Xunming Ji, Yun Xu, Zengqiang Yuan

Research output: Contribution to journalArticle

Abstract

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 IκBα at residues S32 and S36. We further demonstrate that Src kinase functions upstream of MST1–IκB signaling during microglial activation. Specific deletion of MST1 in microglia mitigates stroke-induced brain injury. Therefore, we propose that Src–MST1–IκB 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.

Original languageEnglish (US)
Pages (from-to)236-248
Number of pages13
JournalBrain, Behavior, and Immunity
Volume55
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

Keywords

  • Hippo/MST1
  • Ischemia
  • IκB
  • Microglia
  • Src

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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  • Cite this

    Zhao, S., Yin, J., Zhou, L., Yan, F., He, Q., Huang, L., Peng, S., Jia, J., Cheng, J., Chen, H., Tao, W., Ji, X., Xu, Y., & Yuan, Z. (2016). Hippo/MST1 signaling mediates microglial activation following acute cerebral ischemia–reperfusion injury. Brain, Behavior, and Immunity, 55, 236-248. https://doi.org/10.1016/j.bbi.2015.12.016