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The Journal of Neuroscience, August 5, 2009, 29(31):9839-9849; doi:10.1523/JNEUROSCI.2496-09.2009

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

Brenda Marsh,¹ Susan L. Stevens,¹ Amy E. B. Packard,¹ Banu Gopalan,³ Brian Hunter,¹ Philberta Y. Leung,¹ Christina A. Harrington,² and Mary P. Stenzel-Poore¹

¹Department of Molecular Microbiology and Immunology and ²Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, Oregon 97239, and ³Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195

Correspondence should be addressed to Dr. Mary P. Stenzel-Poore, Department of Molecular Microbiology and Immunology, L220, Oregon Health & Science University, 3181 Sam Jackson Park Road, Portland, OR 97239. Email: poorem{at}ohsu.edu

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.

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Received May 26, 2009; revised June 29, 2009; accepted June 30, 2009.

Correspondence should be addressed to Dr. Mary P. Stenzel-Poore, Department of Molecular Microbiology and Immunology, L220, Oregon Health & Science University, 3181 Sam Jackson Park Road, Portland, OR 97239. Email: poorem{at}ohsu.edu

This article has been cited by other articles:

				R. A. Hegele and M. Dichgans Advances in Stroke 2009: Update on the Genetics of Stroke and Cerebrovascular Disease 2009 Stroke, February 1, 2010; 41(2): e63 - e66. [Full Text] [PDF]

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