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