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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS076620-04
Application #
8712571
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Bosetti, Francesca
Project Start
2011-09-15
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
$334,588
Indirect Cost
$118,026
Name
University of Washington
Department
Neurology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Su, Wei; Hopkins, Stephanie; Nesser, Nicole K et al. (2014) The p53 transcription factor modulates microglia behavior through microRNA-dependent regulation of c-Maf. J Immunol 192:358-66
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