The glial response to CNSHIV infection includes p53 activation and increased expression of p53 target genes
The glial response to CNSHIV infection includes p53 activation and increased expression of p53 target genes
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DOI：
10.1007/s11481-007-9095-x
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发表时间：
2007-12-01
影响因子：
6.2
通讯作者：
Garden, Gwenn A.
中科院分区：
文献类型：
--
作者：
Jayadev, Suman;Yun, Bomy;Garden, Gwenn A.
HIV相关痴呆（HAD）是一种慢性神经炎症性疾病，在没有合理治疗的情况下仍然是一个重要的临床问题。由于 HIV 不感染神经元，因此 HAD 的发病机制被认为继发于受感染白细胞的影响，包括实质小胶质细胞，其可以分泌炎症介质和病毒产物，从而改变周围未感染细胞的功能。我们之前报道过转录因子 p53 在 HAD 患者的神经元、小胶质细胞和星形胶质细胞中积累。我们还表明，p53 缺陷小鼠的小胶质细胞在共培养系统中无法诱导对 HIV 外壳蛋白 gp120 的神经毒性反应，这支持了 p53 在 HIV 相关神经变性的慢性神经炎症成分中发挥致病作用的假设。我们分析了 10 名 AIDS 患者皮层下白质中 p53 积累的程度和细胞类型特异性，这些患者先前已被证明白质 p53 积累。为了确定 p53 激活是否会改变 HAD 中的基因表达，皮层组织切片还对 p53 靶基因 Bax 和 p2(WAF1) 进行了免疫标记。这些研究表明，小胶质细胞、星形胶质细胞和少突胶质细胞均在 HIV 感染后表现出 p53 激活。我们观察到 p53 免疫反应性升高的患者神经元和神经胶质细胞中 Bax 和 p21 (WAF1) 的免疫反应性。我们的研究结果表明 HAD 中存在广泛增加的 p53 表达。 HAD 患者神经胶质细胞中 p53 介导的通路的激活可能会通过抑制神经胶质细胞增殖和/或促进神经胶质细胞功能障碍来促进神经炎症过程，从而促进神经退行性变。
HIV-associated dementia (HAD) is a chronic neuroinflammatory disease that remains an important clinical problem without available rational treatment. As HIV does not infect neurons, the pathogenesis of HAD is thought to be secondary to the impact of infected leukocytes, including parenchymal microglia, which can secrete inflammatory mediators and viral products that alter the function of surrounding uninfected cells. We previously reported that the transcription factor p53 accumulates in neurons, microglia, and astrocytes of HAD patients. We have also shown that microglia from p53-deficient mice fail to induce neurotoxicity in response to the HIV coat protein gp120 in a coculture system, supporting the hypothesis that p53 plays a pathogenic role in the chronic neuroinflammatory component of HIV-associated neurodegeneration. We analyzed the extent and cell type specificity of p53 accumulation in subcortical white matter of ten AIDS patients that had previously been shown to demonstrate white matter p53 accumulation. To determine if p53 activation functioned to alter gene expression in HAD, cortical tissue sections were also immunolabeled for the p53 target genes Bax and p2(WAF1). These studies reveal that microglia, astrocytes, and oligodendrocytes all demonstrate p53 activation in response to HIV infection. We observed immunoreactivity for both Bax and p21(WAF1) in neurons and glia from patients demonstrating elevated p53 immunoreactivity. Our findings demonstrate that widespread increased p53 expression is present in HAD. Activation of p53 mediated pathways in the glia of HAD patients may contribute to the neuroinflammatory processes that promote neurodegeneration by inhibiting glial proliferation and/or promoting glial cell dysfunction.