Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke

A critical role for IRF3

Brenda Marsh, Susan L. Stevens, Amy E B Packard, Banu Gopalan, Brian Hunter, Philberta Y. Leung, Christina (Chris) Harrington, Mary Stenzel-Poore

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury through activation of its receptor, Toll-like receptor 4 (TLR4). Paradoxically, TLR activation by endogenous ligands after ischemia worsens stroke damage. Here, we define a novel, protective role for TLRs after ischemia in the context of LPS preconditioning. Microarray analysis of brains collected 24 h after stroke revealed a unique set of upregulated genes in LPS-pretreated animals. Promoter analysis of the unique gene set identified an overrepresentation of type I interferon (IFN)-associated transcriptional regulatory elements. This finding suggested the presence of type I IFNs or interferon regulatory factors (IRFs), which upregulate interferon-stimulated genes. Upregulation of IFNβ was confirmed by real-time reverse transcription-PCR. Direct administration of IFNβ intracerebroventricularly at the time of stroke was sufficient for neuroprotection. TLR4 can induce both IFNβ and interferon-stimulated genes through its adapter molecule Toll/interleukin receptor domain-containing adaptor-inducing IFNβ (TRIF) and the IRF3 transcription factor. We show in oxygen glucose deprivation of cortical neurons, an in vitro model of stroke, that activation of TRIF after stroke reduces neuronal death. Furthermore, mice lacking IRF3 were not protected by LPS preconditioning in our in vivo model. Our studies constitute the first demonstration of the neuroprotective capacity of TRIF/IRF3 signaling and suggest that interferon-stimulated genes, whether induced by IFNβ or by enhanced TLR signaling to IRF3, are a potent means of protecting the brain against ischemic damage.

Original languageEnglish (US)
Pages (from-to)9839-9849
Number of pages11
JournalJournal of Neuroscience
Volume29
Issue number31
DOIs
StatePublished - Aug 5 2009

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Brain Injuries
Interferons
Lipopolysaccharides
Stroke
Brain
Toll-Like Receptor 4
Genes
Up-Regulation
Ischemia
Transcriptional Regulatory Elements
Interleukin Receptors
Interferon Regulatory Factors
Interferon Type I
Microarray Analysis
Reverse Transcription
Transcription Factors
Oxygen
Ligands
Neurons
Glucose

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke : A critical role for IRF3. / Marsh, Brenda; Stevens, Susan L.; Packard, Amy E B; Gopalan, Banu; Hunter, Brian; Leung, Philberta Y.; Harrington, Christina (Chris); Stenzel-Poore, Mary.

In: Journal of Neuroscience, Vol. 29, No. 31, 05.08.2009, p. 9839-9849.

Research output: Contribution to journalArticle

Marsh, Brenda ; Stevens, Susan L. ; Packard, Amy E B ; Gopalan, Banu ; Hunter, Brian ; Leung, Philberta Y. ; Harrington, Christina (Chris) ; Stenzel-Poore, Mary. / Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke : A critical role for IRF3. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 31. pp. 9839-9849.
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