Multiple preconditioning paradigms converge on interferon regulatory factor-dependent signaling to promote tolerance to ischemic brain injury

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 ischemiain mice confers substantial protection against ischemic damage.Toelucidate the molecular mechanisms of preconditioning,wecompared brain genomic profilesinresponsetopreconditioningwith these TLR ligands andwith preconditioning via exposure to brief ischemia. We found that exposure to the TLR ligands and brief ischemia induced genomic changes in the brain characteristicofaTLRpathway-mediatedresponse.Interestingly,allthreepreconditioningstimuliresultedinareprogrammed response to stroke injury that convergedonashared subsetof13genes not evidentinthe genomic profile from brainsthat were subjectedtostroke 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 showthatboth transcription factors are requiredfor TLR-mediatedpreconditioningand neuroprotection.Thesestudiesare the first to discovera convergent mechanism of neuroprotection induced bypreconditioning-one that potentially results inreprogramming of the TLR-mediated response to stroke and requires the presence of IRF3 and IRF7.