CD200 signaling mediates the interactions of neurons and endothelia with circulating leukocytes in stroke

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PROJECT SUMMARY Immune responses are a fundamental pathophysiological process that significantly contribute to ischemic brain injury. Holding the immune response in check can alleviate the delayed injury seen in stroke and has considerable translational value. CD200 binds to its receptor, CD200R, that is expressed on immune cells. This forms an endogenous inhibitory signal and reduces the activation of immune cells. The traditional notion that the neuronal-microglial CD200-CD200R interaction is the key to suppressing deleterious immune activation has been increasingly questioned, as accumulating data has shown that the CD200R is expressed on peripheral immune cells but not on adult microglia. In this proposal we hypothesize that the CD200-CD200R signaling axis inhibits mobilization of peripheral immune cells after stroke, and that interruption of CD200-CD200R interaction will exacerbate both central (brain) and peripheral immune responses. We will specifically examine the CD200-CD200R axis from both ends, by manipulating either CD200 or the CD200R to determine the effects on peripheral immune cell activation and stroke injury. In Aim 1, we will use a bone marrow chimera mouse model generated from global CD200R knockout and GFP+ mice, to determine the contribution of peripheral vs. central (brain) CD200- CD200R signaling to stroke outcomes. Aim 2 will investigate the effect of endothelial CD200 signaling on peripheral leukocyte migration in the ischemic brain. Brain endothelial CD200 knockdown (by AAV-BR1-Cre virus) and lenti-CD200 virus (conjugated with endothelial specific promotor Cadherin 5) transfected mice will be used to examine the effects of down-/up-regulation of endothelial CD200 respectively on immune responses to stroke. Aim 3 will evaluate the role of neuronal CD200 signaling in post-stroke inflammation and stroke outcomes. Neuronal CD200 CKO mice (CD200fl/fl:Eno2-Cre) and lenti-CD200 virus on neuronal promotor Enolase 2 (Eno2) will be used. As CD200-CD200R signaling functions in various neuroinflammatory diseases, the proposed project will open up a new area of CD200-CD200R research not only in stroke, but also in other central nervous system disorders.