title: Multiple preconditioning paradigms converge on interferon regulatory factor-dependent signaling to promote tolerance to ischemic brain injury.
abstract: Ischemic tolerance can be induced by numerous preconditioning stimuli, including various Toll-like receptor (TLR) ligands. We have shown previously that systemic administration of the TLR4 ligand LPS or the TLR9 ligand unmethylated CpG oligodeoxynucleotide before transient brain ischemia in mice confers substantial protection against ischemic damage. To elucidate the molecular mechanisms of preconditioning, we compared brain genomic profiles in response to preconditioning with these TLR ligands and with preconditioning via exposure to brief ischemia. We found that exposure to the TLR ligands and brief ischemia induced genomic changes in the brain characteristic of a TLR pathway-mediated response. Interestingly, all three preconditioning stimuli resulted in a reprogrammed response to stroke injury that converged on a shared subset of 13 genes not evident in the genomic profile from brains that were subjected to stroke without prior preconditioning. Analysis of the promoter region of these shared genes showed sequences required for interferon regulatory factor (IRF)-mediated transcription. The importance of this IRF gene network was tested using mice deficient in IRF3 or IRF7. Our data show that both transcription factors are required for TLR-mediated preconditioning and neuroprotection. These studies are the first to discover a convergent mechanism of neuroprotection induced by preconditioning--one that potentially results in reprogramming of the TLR-mediated response to stroke and requires the presence of IRF3 and IRF7.
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon 97239, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Stevens
authors.forename: Philberta Y
authors.initials: PY
authors.lastname: Leung
authors.forename: Keri B
authors.initials: KB
authors.lastname: Vartanian
authors.forename: Banu
authors.initials: B
authors.lastname: Gopalan
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Roger P
authors.initials: RP
authors.lastname: Simon
authors.forename: Mary P
authors.initials: MP
authors.lastname: Stenzel-Poore
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000276:immunology*; D002545:Brain Ischemia / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression / Q000187:drug effects; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology*; D019194:Ischemic Preconditioning / Q000379:methods*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*
chemical_list: D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors