Notch activation enhances the microglia-mediated inflammatory response associated with focal cerebral ischemia

Wei, Zelan, Chigurupati, Srinivasulu, Arumugam, Thiruma V., Jo, Dong-Gyu, Li, He and Chan, Sic L. (2011) Notch activation enhances the microglia-mediated inflammatory response associated with focal cerebral ischemia. Stroke, 42 9: 2589-2594. doi:10.1161/STROKEAHA.111.614834


Author Wei, Zelan
Chigurupati, Srinivasulu
Arumugam, Thiruma V.
Jo, Dong-Gyu
Li, He
Chan, Sic L.
Title Notch activation enhances the microglia-mediated inflammatory response associated with focal cerebral ischemia
Journal name Stroke   Check publisher's open access policy
ISSN 0039-2499
1524-4628
Publication date 2011-09-01
Sub-type Article (original research)
DOI 10.1161/STROKEAHA.111.614834
Volume 42
Issue 9
Start page 2589
End page 2594
Total pages 6
Place of publication Philadelphia, PA, U.S.A.
Publisher Lippincott Williams & Wilkins
Collection year 2012
Language eng
Formatted abstract
Background and Purpose—Activation of Notch worsens ischemic brain damage as antisense knockdown or pharmacological inhibition of the Notch pathway reduces the infarct size and improves the functional outcome in a mouse model of stroke. We sought to determine whether Notch activation contributes to postischemic inflammation by directly modulating the microglial innate response.

Methods—The microglial response and the attendant inflammatory reaction were evaluated in Notch1 antisense transgenic (Tg) and in nontransgenic (non-Tg) mice subjected to middle cerebral artery occlusion with or without treatment with a γ-secretase inhibitor (GSI). To investigate the impact of Notch on microglial effector functions, primary mouse microglia and murine BV-2 microglial cell line were exposed to oxygen glucose deprivation or lipopolysaccharide in the presence or absence of GSI. Immunofluorescence labeling, Western blotting, and reverse-transcription polymerase chain reaction were performed to measure microglial activation and production of inflammatory cytokines. The nuclear translocation of nuclear factor-κB in microglia was assessed by immunohistochemistry. The neurotoxic potential of microglia was determined in cocultures.

Results—Notch1 antisense mice exhibit significantly lower numbers of activated microglia and reduced proinflammatory cytokine expression in the ipsilateral ischemic cortices compared to non-Tg mice. Microglial activation also was attenuated in Notch1 antisense cultures and in non-Tg cultures treated with GSI. GSI significantly reduced nuclear factor-κB activation and expression of proinflammatory mediators and markedly attenuated the neurotoxic activity of microglia in cocultures.

Conclusions—These findings establish a role for Notch signaling in modulating the microglia innate response and suggest that inhibition of Notch might represent a complementary therapeutic approach to prevent reactive gliosis in stroke and neuroinflammation-related degenerative disorders.
Keyword Apoptosis
Brain ischemia
Focal ischemia
Inflammation
Neuroprotection
Neuroregeneration
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Biomedical Sciences Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 49 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 52 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 02 Sep 2011, 15:06:41 EST by Dr Thiruma V Arumugam on behalf of School of Biomedical Sciences