Abstract TP255: Interferon-Induced Peptide With Tetratricopeptide Repeats 1 Is a Key Mediator of Neuroprotection Induced by Preconditioning

Introduction: Preconditioning is the phenomenon whereby a low dose of a harmful stimulus provides robust protection against injury due to subsequent cerebral ischemia. We have evaluated transcriptional responses in three distinct preconditioning paradigms [lipopolysaccharide (LPS), CpG, brief ischemia] to create an inferred network of the neuroprotective genomic responses to stroke in mice. Topological analysis of this network identified interferon-induced peptide with tetratricopeptide repeats 1 (IFIT1) as a key transition point between clusters of genes, which suggests that IFIT1 is significant in this biological process. IFIT1 has been shown to function as a regulator of protein translation and transcription factor activity, although a role in ischemic injury has not been identified. We hypothesized that IFIT1 is required for neuroprotection against ischemic injury in the setting of preconditioning. Methods: We analyzed the regulation of IFIT1 and its inferred first-order network (genes directly linked to IFIT1) using mouse brain microarray data 3, 24, and 72 h following preconditioning and 3 and 24 h following middle cerebral artery occlusion (MCAO, n=4/treatment/timepoint, ~100 microarrays). In addition, IFIT1 deficient mice were preconditioned with LPS 72 h prior to MCAO and percent infarct was determined. Results: Network analysis revealed that IFIT1 and its first-order network are induced 24 h following stroke in preconditioned mice but not in mice given a stroke in the absence of preconditioning. This result suggests that IFIT1’s first-order network is associated with neuroprotection. Interestingly, IFIT1’s first-order network contains several interferon-associated genes, which are known to contribute to neuroprotection induced by preconditioning. Further support for a fundamental role for IFIT1 is evinced by our finding that IFIT1 deficient mice preconditioned with LPS are not protected against subsequent MCAO. Conclusion: IFIT1 is essential for neuroprotection induced by LPS preconditioning and may play an instrumental role in mediating an endogenous neuroprotective response to stroke.