Immunomodulation and adult neurogenesis after stroke

脑室下区的神经母细胞在中风后显著增殖，并随血管迁移到损伤部位。然而，由于局部炎症，很大一部分中风产生的神经母细胞在出生后不久死亡。e -选择素在内皮细胞上特异性表达，但仅在内皮激活时表达。由于内皮细胞活化发生在中风后，e -选择素可以作为一种免疫耐受抗原，将免疫调节集中在血管树的区域。鼻内滴注重组e -选择素将诱导粘膜对该抗原产生耐受，同时产生e -选择素特异性调节性T细胞（Tregs）。Tregs可能通过“旁观者抑制”保护新生的神经母细胞免受缺血性损伤，其中免疫调节细胞因子如TGF-β和IL-10在局部释放。在本系列实验中，我们发现永久性大脑中动脉闭塞（pMCAO）大鼠经e -选择素耐受后，Tregs向缺血脑梗死周围区转移，局部神经血管生态位中TNF表达降低，梗死周围区新生成神经细胞或神经元存活率增加。在这些条件下，pMCAO后感觉运动功能的改善也会发生。e -选择素特异性treg可以调节缺血后成人神经发生的功效，促进脑损伤后的修复。

Neuroblasts in the subventricular zone proliferate markedly after stroke, and migrate to the site of injury along with blood vessels. However, a large fraction of stroke-generated neuroblasts die shortly after being born, because of local inflammation.E-selectin is specifically expressed on endothelial cells, but only when the endothelium activates. Since endothelial activation occurs after stroke, E-selectin can serve as an immunologic tolerization antigen that can focus immunomodulation to regions of the vascular tree. Intranasal instillation of recombinant E-selectin will induce mucosal tolerance to that antigen with the generation of E-selectin-specific regulatory T cells (Tregs). Tregs may protect newly-generated neuroblasts from ischemic damage through'bystander suppression' in which immunomodulatory cytokines such as TGF-β and IL-10 are released locally. In this series of experiments, we have shown that after E-selectin tolerization in permanent middle cerebral artery occlusion (pMCAO) rats Tregs transmigrate to the peri-infarct region of ischemic brain, TNF expression in the local neurovascular niche is reduced, and the survival of newly generated neuroblasts or neurons in the peri-infarct region is increased. Under these conditions, an improvement in sensorimotor function after pMCAO also occurs.E-selectin-specific Tregs can modulate the efficacy of adult neurogenesis after ischemia and promote repair after brain injury.