Hypoxia-Ischemia Upregulates TRAIL and TRAIL Receptors in the Immature Rat Brain
Hypoxia-Ischemia Upregulates TRAIL and TRAIL Receptors in the Immature Rat Brain
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缺氧缺血上调未成熟大鼠大脑中的 TRAIL 和 TRAIL 受体
DOI：
10.1159/000334475
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发表时间：
2011-01-01
影响因子：
2.9
通讯作者：
Chen, Chao
中科院分区：
文献类型：
--
作者：
Huang, Zhiheng;Song, Lili;Chen, Chao
未成熟的大脑容易受到缺氧缺血（HI）或感染引起的炎性损伤，导致早产幸存者严重的神经发育障碍。近年来，肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）及其受体（死亡受体DR 4/5和诱骗受体DcR 1/2）被报道介导多种神经炎症反应。然而，关于TRAIL及其受体在HI后未成熟脑中的作用的信息很少。本研究的目的是评估TRAIL及其受体在HI后未成熟脑中的表达，并将这种表达与神经功能联系起来。我们在出生后第3天的大鼠中进行右颈总动脉结扎，然后缺氧（6%O2，37°C）2.5小时以诱导HI。在HI后24 h通过免疫染色评估TRAIL及其受体、caspase-3和CD 68标记的小胶质细胞/巨噬细胞的分布。Western blot和实时荧光定量PCR分别检测TRAIL和DR 5的蛋白和mRNA表达。HI后7天通过NeuN和Nissl染色评价迟发性神经元损失。此外，通过翻正反射试验、睁眼时间和T-迷宫试验评价神经功能缺损。HI后24 h，同侧大脑半球TRAIL、DR 5和DcR 1/2受体及caspase-3的表达较对侧和对照组明显。HI后24 h，在同侧半球可见DR 5/活性caspase-3双阳性细胞，而在对侧半球未见。TRAIL和CD 68双标记细胞在同侧皮质区比对侧相应区域更明显。HI后24 h TRAIL和DR 5蛋白及mRNA表达显著增加，与HI后7 d神经细胞丢失相对应。此外，与对照组相比，HI组显示出神经行为发育受损（p < 0.05）。总之，我们的研究结果表明，TNF-α超家族配体TRAIL在围产期HI后在CD 68+小胶质细胞/巨噬细胞上被诱导，并且其受体之一DR 5在新皮质神经元和胶质细胞上被诱导。许多DR 5+细胞也是半胱天冬酶-3+，这有力地支持了以下结论：这些信号分子参与了新皮质中神经元的延迟损失和围产期HI后常见的神经行为缺陷。
The immature brain is susceptible to inflammatory injury induced by hypoxia-ischemia (HI) or infection, which causes serious neurodevelopmental disabilities in the survivors of preterm births. Recently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (death receptor DR4/5 and decoy receptor DcR1/2) were reported to mediate various neuroinflammatory responses. However, little information is available regarding the role of TRAIL and its receptors in the immature brain after HI. The purpose of this study was to evaluate the expression of TRAIL and its receptors in the immature brain after HI and relate this expression to neurological function. We performed right common carotid artery ligation followed by hypoxia (6% O2, 37°C) for 2.5 h to induce HI in postnatal day 3 rats. The distribution of TRAIL and its receptors, caspase-3 and CD68-labeled microglia/macrophages was evaluated 24 h after HI by immunostaining. The protein and mRNA expression of TRAIL and DR5 was measured by Western blot and real-time PCR, respectively. Delayed neuronal loss was evaluated by NeuN and Nissl staining 7 days after HI. Furthermore, neurological deficits were evaluated by a righting reflex test, time of eye opening and T-maze test. The expression of TRAIL, DR5 and DcR1/2 receptors and caspase-3 was more pronounced in the ipsilateral hemisphere compared with the contralateral part and the control group 24 h after HI. DR5/active caspase-3 double-positive cells were observed at 24 h after HI in the ipsilateral hemisphere but not in the contralateral hemisphere. The TRAIL and CD68 double-labeled cells were more pronounced in the ipsilateral cortical regions compared with the corresponding regions of the contralateral part. HI also resulted in a significant increase in TRAIL and DR5 protein and mRNA expression at 24 h, which corresponded to neuronal cell loss 7 days after HI. Furthermore, the HI group displayed impaired neurobehavioral development compared with the control group (p < 0.05). Altogether our results show that the TNF-α superfamily ligand TRAIL is induced on CD68+ microglia/macrophages after perinatal HI and that one of its receptors, DR5, is induced on neocortical neurons and glial cells. That many DR5+ cells were also caspase-3+ strongly supports the conclusion that these signaling molecules are involved in the delayed loss of neurons in the neocortex and in the neurobehavioral deficits that are often seen after perinatal HI.