Neuroprotection against stroke injury can be induced by a small dose of lipopolysaccharide (LPS) given systemically prior to a stroke-a process known as LPS preconditioning or tolerance. As such, the study of LPS-induced preconditioning offers promise in identifying new mediators that can be administered systemically to confer neuroprotection centrally. The primary goal of this application is to investigate LPS preconditioning in stroke and define the specific molecular pathways that sub serve this neuroprotective process. Preliminary data suggest that LPS preconditioning leads to decreased cellular infiltration into the injured ischemic brain and suppressed cellular activation, which suggests that LPS preconditioning alters cellular responsiveness to subsequent injurious stimuli. Low dose LPS treatment of macrophages renders them resistant to the damage of subsequent high dose LPS challenge via a shift in the balance of proinflammatory/anti-inflammatory mediators referred to as genomic 'reprogramming'. Experiments in this proposal shall examine whether LPS preconditioning confers protection to subsequent ischemic injury by reprogramming the response to injury away from cell death and in favor of cell survival. TNF-alpha is an essential mediator in LPS preconditioning and may prime the events that lead to protection following stroke. Our preliminary data following stroke indicate that additional, unique pathways are induced in the brains of animals given prior LPS treatment compared to those not so treated. Interferon-associated genes are a dominant feature among the unique genes upregulated in animals given LPS treatment prior to a stroke. We hypothesize that TNF-alpha and Type I IFNs play essential, non-overlapping roles that lead to neuroprotection in LPS preconditioning. We postulate that LPS-induced TNF-alpha primes the emergence of tolerance by reprogramming the cellular response to subsequent ischemia from one of injury and cell death to that of survival. Subsequently, pathways regulated by Type 1 IFNs are activated which confer neuroprotection. Using in vivo and in vitro models of ischemic tolerance we propose to: 1) Elucidate the role of TNF-alpha signaling in priming the neuroprotective events following LPS preconditioning;2) Determine whether Type I IFNs play a critical role in establishing a neuroprotective state following ischemic injury in LPS preconditioned mice;and 3) Test whether LPS preconditioning leads to genomic reprogramming of the response to ischemic injury. These studies should help clarify the endogenous mediators of neuroprotection induced by LPS and may ultimately lead to new therapeutic strategies for stroke.
| Gesuete, Raffaella; Stevens, Susan L; Stenzel-Poore, Mary P (2016) Role of Circulating Immune Cells in Stroke and Preconditioning-Induced Protection. Acta Neurochir Suppl 121:39-44 |
| Gesuete, Raffaella; Christensen, Sara N; Bahjat, Frances R et al. (2016) Cytosolic Receptor Melanoma Differentiation-Associated Protein 5 Mediates Preconditioning-Induced Neuroprotection Against Cerebral Ischemic Injury. Stroke 47:262-6 |
| Vartanian, Keri B; Mitchell, Hugh D; Stevens, Susan L et al. (2015) CpG preconditioning regulates miRNA expression that modulates genomic reprogramming associated with neuroprotection against ischemic injury. J Cereb Blood Flow Metab 35:257-66 |
| Gesuete, Raffaella; Kohama, Steven G; Stenzel-Poore, Mary P (2014) Toll-like receptors and ischemic brain injury. J Neuropathol Exp Neurol 73:378-86 |
| Stevens, Susan L; Vartanian, Keri B; Stenzel-Poore, Mary P (2014) Reprogramming the response to stroke by preconditioning. Stroke 45:2527-31 |
| Lanekoff, Ingela; Stevens, Susan L; Stenzel-Poore, Mary P et al. (2014) Matrix effects in biological mass spectrometry imaging: identification and compensation. Analyst 139:3528-32 |
| Bahjat, Frances R; Gesuete, Raffaella; Stenzel-Poore, Mary P (2013) Steps to translate preconditioning from basic research to the clinic. Transl Stroke Res 4:89-103 |
| Packard, Amy E B; Leung, Philberta Y; Vartanian, Keri B et al. (2012) TLR9 bone marrow chimeric mice define a role for cerebral TNF in neuroprotection induced by CpG preconditioning. J Cereb Blood Flow Metab 32:2193-200 |
| McDermott, Jason E; Vartanian, Keri B; Mitchell, Hugh et al. (2012) Identification and validation of Ifit1 as an important innate immune bottleneck. PLoS One 7:e36465 |
| Leung, Philberta Y; Stevens, Susan L; Packard, Amy E B et al. (2012) Toll-like receptor 7 preconditioning induces robust neuroprotection against stroke by a novel type I interferon-mediated mechanism. Stroke 43:1383-9 |
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