RRC ID 11821
Author Marsh B, Stevens SL, Packard AE, Gopalan B, Hunter B, Leung PY, Harrington CA, Stenzel-Poore MP.
Title Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3.
Journal J. Neurosci.
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 IFNbeta was confirmed by real-time reverse transcription-PCR. Direct administration of IFNbeta intracerebroventricularly at the time of stroke was sufficient for neuroprotection. TLR4 can induce both IFNbeta and interferon-stimulated genes through its adapter molecule Toll/interleukin receptor domain-containing adaptor-inducing IFNbeta (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 IFNbeta or by enhanced TLR signaling to IRF3, are a potent means of protecting the brain against ischemic damage.
Volume 29(31)
Pages 9839-49
Published 2009-8-5
DOI 10.1523/JNEUROSCI.2496-09.2009
PII 29/31/9839
PMID 19657036
PMC PMC2946887
MeSH Animals Brain / drug effects Brain / metabolism Cell Death / drug effects Cell Hypoxia / drug effects Gene Expression / drug effects Glucose / deficiency Infarction, Middle Cerebral Artery / drug therapy* Interferon Regulatory Factor-3 / genetics Interferon Regulatory Factor-3 / metabolism* Interferon-beta / genetics Interferon-beta / metabolism Interferon-beta / therapeutic use* Lipopolysaccharides / administration & dosage* Male Mice Mice, Inbred C57BL Mice, Knockout Neurons / drug effects Neurons / physiology Neuroprotective Agents / administration & dosage* Oligonucleotide Array Sequence Analysis Reperfusion Injury / prevention & control*
IF 6.074
Times Cited 103
Mice IRF-3 Knockout mice C57BL/6J