Ischemic preconditioning (IPC) in the brain is a robust neuroprotective phenomenon in which a brief ischemic exposure increases resistance to the injurious effects of subsequent prolonged ischemia. Characterizing the cellular and molecular mechanisms of IPC is an active area of investigation in stroke research. Microglia, the brain's specialized tissue macrophages, play a major role in the neuroinflammatory response and in many neurological diseases including stroke. Several lines of evidence support a role for microglia in IPC. Microglia express Toll-like receptors (TLRs) that mediate powerful immune responses to exogenous and endogenous agonists. TLR4 is required for IPC-induced neuroprotection. In order to elucidate the mechanisms by which microglial TLR4 contributes to IPC, we carried out cell-targeted genomic analyses specifically on microglia exposed to either ischemic conditions in vitro or IPC in vivo. Results from both datasets identified robust expression of type 1 and/or type 3 interferon (IFN)-stimulated genes (ISGs) as the predominant transcriptomal feature of ischemia-exposed WT, but not TLR4-/-, microglia. The IFN family of cytokines is recognized as a key component of the innate immune response to infection. Recent work has implicated microglial IFN signaling as an important regulator of the injury response induced by non-infectious mechanisms. The focus of this proposal is to characterize the role of type 1 &3 IFNs in mediating the IPC phenomenon and the microglial response to ischemia using both in vitro (hypoxia/hypoglycemia treatment of primary microglia) and in vivo (middle cerebral artery occlusion/reperfusion) experimental models.
Stroke is the leading cause of serious long-term disability and the third leading cause of death in the United States. Currently available pharmacologic therapies for acute stroke are few in number and limited in efficacy. A major goal of this research project is to increase our mechanistic understanding of stroke pathophysiology. In doing so, we seek to identify novel cellular and molecular targets for more effective pharmacotherapy.
|Singh, Tarvinder P; Weinstein, Jonathan R; Murphy, Sean P (2017) Stroke: Basic and Clinical. Adv Neurobiol 15:281-293|
|McDonough, Ashley; Lee, Richard V; Noor, Shahani et al. (2017) Ischemia/Reperfusion Induces Interferon-Stimulated Gene Expression in Microglia. J Neurosci 37:8292-8308|
|McDonough, Ashley; Lee, Richard V; Weinstein, Jonathan R (2017) Microglial Interferon Signaling and White Matter. Neurochem Res 42:2625-2638|
|Staal, Roland G W; Weinstein, Jonathan R; Nattini, Megan et al. (2017) Senicapoc: Repurposing a Drug to Target Microglia KCa3.1 in Stroke. Neurochem Res 42:2639-2645|
|McDonough, Ashley; Weinstein, Jonathan R (2016) Neuroimmune Response in Ischemic Preconditioning. Neurotherapeutics 13:748-761|
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|Weinstein, Jonathan R; Quan, Yi; Hanson, Josiah F et al. (2015) IgM-Dependent Phagocytosis in Microglia Is Mediated by Complement Receptor 3, Not Fc?/? Receptor. J Immunol 195:5309-17|
|Hamner, Margaret A; Ye, Zucheng; Lee, Richard V et al. (2015) Ischemic Preconditioning in White Matter: Magnitude and Mechanism. J Neurosci 35:15599-611|
|Becker, Kyra; Kohen, Ruth; Lee, Richard et al. (2015) Poststroke fatigue: hints to a biological mechanism. J Stroke Cerebrovasc Dis 24:618-21|
|Weinstein, Jonathan R; Schulze, Juliane; Lee, Richard V et al. (2014) Functional polymorphisms in toll-like receptor 4 are associated with worse outcome in acute ischemic stroke patients. Neuroreport 25:580-4|
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