Systemic Lipopolysaccharide Protects the Brain from Ischemic Injury by Reprogramming the Response of the Brain to Stroke: A Critical Role for IRF3

• DOI: 10.1523/jneurosci.2496-09.2009
• Publication Date: 2009-08-05T17:33:40Z
• Authors: Brenda Marsh; Susan L. Stevens; Amy E. B. Packard; Banu Gopalan; Brian Hunter; Philberta Y. Leung; Christina A. Harr...; Mary P. Stenzel-P...
• Keywords: TRIF; IRF3; HMGB1

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