Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke.
Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke.
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DOI：
10.1038/cdd.2011.145
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发表时间：
2012-05
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
作者：
越来越多的证据表明，免疫反应影响损伤脑的修复机制。最近，我们已经证明CD4+T细胞在中风后的神经发生中起负调节作用，但其机制细节尚不清楚。糖皮质激素诱导的肿瘤坏死因子（TNF）受体（GITR）是一种多方面的免疫调节剂，属于TNF受体超家族，在活化的CD4+T细胞上表达。在此，我们通过小鼠皮质梗死模型表明，GITR对CD4+T细胞的触发增加了卒中后炎症，减少了缺血诱导的神经干/祖细胞（iNSPCs）的数量。CD4+GITR+T细胞优先积聚在脑缺血后皮层，GITR刺激抗体处理小鼠脑卒中后炎症反应增强，insc凋亡增强。相反，通过GITR-Fc融合蛋白阻断GITR-GITR配体（GITRL）相互作用可消除炎症并抑制iNSPCs的凋亡。此外，gitr刺激的T细胞引起了iNSPC的凋亡，与未刺激的T细胞相比，gitr刺激的T细胞显著降低了中风后严重联合免疫缺陷小鼠的iNSPC数量。这些观察结果表明，在CD4+T细胞中，GITR+CD4+T细胞是脑卒中后神经发生的主要恶化调节剂。这表明阻断GITR-GITRL相互作用可能是一种新的基于免疫的中风治疗方法。
Increasing evidences show that immune response affects the reparative mechanisms in injured brain. Recently, we have demonstrated that CD4+T cells serve as negative modulators in neurogenesis after stroke, but the mechanistic detail remains unclear. Glucocorticoid-induced tumor necrosis factor (TNF) receptor (GITR), a multifaceted regulator of immunity belonging to the TNF receptor superfamily, is expressed on activated CD4+T cells. Herein, we show, by using a murine model of cortical infarction, that GITR triggering on CD4+T cells increases poststroke inflammation and decreases the number of neural stem/progenitor cells induced by ischemia (iNSPCs). CD4+GITR+T cells were preferentially accumulated at the postischemic cortex, and mice treated with GITR-stimulating antibody augmented poststroke inflammatory responses with enhanced apoptosis of iNSPCs. In contrast, blocking the GITR–GITR ligand (GITRL) interaction by GITR–Fc fusion protein abrogated inflammation and suppressed apoptosis of iNSPCs. Moreover, GITR-stimulated T cells caused apoptosis of the iNSPCs, and administration of GITR-stimulated T cells to poststroke severe combined immunodeficient mice significantly reduced iNSPC number compared with that of non-stimulated T cells. These observations indicate that among the CD4+T cells, GITR+CD4+T cells are major deteriorating modulators of poststroke neurogenesis. This suggests that blockade of the GITR–GITRL interaction may be a novel immune-based therapy in stroke.
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影响因子：
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