Emerging data suggests that stroke-induced inflammation significantly contributes to neuronal injury and clinical outcome. Local inflammatory responses following cerebral ischemia have highlighted a pivotal role for the innate immune system in the brain's response to injury, including the activation of microglia and macrophages. Cell-surface receptors (e.g., CD200R1) on microglia and other myeloid-derived cells directly interact with specific endogenous ligands (e.g ., CD200) expressed on neurons and act to suppress pro- inflammatory signaling by maintaining microglia in a """"""""resting state"""""""". Normally these inhibitory mechanisms are required to keep the brain an immune-privileged site. When these interactions are broken, however, microglia can become disinhibited and enter a state of tonic activation, thereby exacerbating injury and worsening outcome. Thus, regulation of microglia after injury is crucial. Recent studies investigating the imbalance of CD200-CD200R1 signaling in models of neurodegenerative disease support the hypothesis that this interaction may also be disrupted following stroke. Preliminary data from our lab suggests that CD200 protein expression levels are decreased in the ischemic hemisphere early after experimental stroke, indicating that the inhibitory 'brake'on microglia is removed. Interestingly, we show a concurrent increase in CD200R1 protein levels after stroke, which coincided with an increased number of activated microglia and peripheral leukocyte recruitment. In this proposal we intend to elucidate the role of CD200-CD200R1 inhibitory signaling in stroke.
In Aim 1 we will explore the functional consequences of these neuronal-glial interactions using conditional neuronal CD200 knockout and CD200R1 (global) knockout mice.
Aim 2 will continue our mechanistic study of CD200R1- mediated inhibition by examining the local (microglia) and peripheral (leukocyte) contributions to stroke using CD200R1-/- bone marrow chimeras. Finally, Aim 3 will employ a small molecule CD200R1 agonist (CD200-Fc) for proof-of-principle of a therapeutic strategy to treat stroke. The overall goal of this proposal is to investigate the immunoregulatory mechanisms underlying microglia activation in brain injury and determine the efficacy of temporally suppressing microglia/myeloid activation to promote better outcomes and enhance recovery after stroke.

Public Health Relevance

Stroke is the fourth leading cause of death and primary cause of disability in the U.S. Despite the major global health and economic burden, currently there is only one FDA-approved drug for ischemic stroke. However, due to its narrow therapeutic window of 4.5 hours and the many exclusion criteria for its use, the need to develop new strategies with wider treatment windows is paramount. This proposal will examine the immunoregulatory pathways involved in the inflammatory response to ischemic stroke and seeks to define new targets for treatment.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Bosetti, Francesca
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University of Connecticut
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Ritzel, Rodney M; Patel, Anita R; Spychala, Monica et al. (2017) Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk. Proc Natl Acad Sci U S A 114:E5673-E5682
Crapser, Joshua; Ritzel, Rodney; Verma, Rajkumar et al. (2016) Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice. Aging (Albany NY) 8:1049-63
Ritzel, Rodney M; Crapser, Joshua; Patel, Anita R et al. (2016) Age-Associated Resident Memory CD8 T Cells in the Central Nervous System Are Primed To Potentiate Inflammation after Ischemic Brain Injury. J Immunol 196:3318-30
Ritzel, Rodney M; Pan, Sarah J; Verma, Rajkumar et al. (2016) Early retinal inflammatory biomarkers in the middle cerebral artery occlusion model of ischemic stroke. Mol Vis 22:575-88
Ritzel, Rodney M; Patel, Anita R; Grenier, Jeremy M et al. (2015) Functional differences between microglia and monocytes after ischemic stroke. J Neuroinflammation 12:106
Ritzel, Rodney M; Patel, Anita R; Pan, Sarah et al. (2015) Age- and location-related changes in microglial function. Neurobiol Aging 36:2153-63
Mirza, Mehwish A; Ritzel, Rodney; Xu, Yan et al. (2015) Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy. J Neuroinflammation 12:32
Ritzel, Rodney M; Capozzi, Lori A; McCullough, Louise D (2013) Sex, stroke, and inflammation: the potential for estrogen-mediated immunoprotection in stroke. Horm Behav 63:238-53
Patel, Anita R; Ritzel, Rodney; McCullough, Louise D et al. (2013) Microglia and ischemic stroke: a double-edged sword. Int J Physiol Pathophysiol Pharmacol 5:73-90