Mucosal Tolerance to E-Selectin Promotes the Survival of Newly Generated Neuroblasts via Regulatory T-Cell Induction after Stroke in Spontaneously Hypertensive Rats

Neuroblasts in the subventricular zone (SVZ) proliferate markedly after brain ischemia, and migrate to the site of injury along with blood vessels. However, a large fraction of stroke-generated neuroblasts die shortly after being born, in part, because of local inflammation. In spontaneously hypertensive rats (SHRs) subjected to permanent middle cerebral artery occlusion, we primed E-selectin-specific regulatory T cells (Tregs) by repetitive intranasal administration of recombinant E-selectin to target local secretion of immunomodulating, antiinflammatory cytokines to activating blood vessel segments. E-selectin-tolerized SHRs had decreased infarction volumes, and increased numbers of Tregs in the cervical lymph nodes and ischemic brain. The brain Tregs were distributed primarily in periinfarct regions. E-selectin tolerization did not alter cellular proliferation in the ipsilateral SVZ after stroke, but the expression of tumor necrosis factor on vascular niche blood vessels was suppressed and both doublecortin protein levels and the number of newly generated neuroblasts or neurons were increased in the brain. This enhanced survival of neural progenitor cells and neurons was paralleled by improved functional performance. These studies suggest that E-selectin-specific Tregs can modulate the efficacy of neurogenesis after ischemia and promote repair after brain injury.