Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection
Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection
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DOI：
10.4049/jimmunol.174.11.7320
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发表时间：
2005-06-01
影响因子：
4.4
通讯作者：
Power, C
中科院分区：
文献类型：
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作者：
Noorbakhsh, F;Vergnolle, N;Power, C
蛋白酶激活受体（PARS）是新近发现的g蛋白偶联受体亚群，在神经细胞中广泛表达，但其在神经系统中的作用尚不清楚。在这项研究中，我们报告了PAR-2在神经元上的上调，与hiv -1相关痴呆患者脑组织中的神经炎症有关。炎症因子tnf - α和IL-1 β在hiv -1相关的痴呆患者的大脑中也比没有痴呆的患者增加（p < 0.05），但这些细胞因子诱导神经元上PAR-2的表达。PAR-2表达的增强和随后的激活阻止了由hiv编码蛋白Tat引起的神经元细胞死亡和肿瘤抑制因子p53的诱导（P < 0.01）。在一个HIV神经发病的小鼠模型中，腭腔内植入PAR-2肽激动剂也能抑制tat诱导的神经毒性（p < 0.05）。此外，PAR-2缺失动物的Tat神经毒性引起的神经炎症和神经元损失更为严重（p < 0.05）。TNF-a保护野生型神经元免受tat相关的神经毒性，但在par -2缺失的神经元中，相同浓度的tnf - α具有细胞毒性（p < 0.001）。因此，神经炎症可以发挥保护作用，通过诱导PAR-2表达，从而消除神经元死亡。
Proteinase-activated receptors (PARS), a newly discovered subgroup of G-protein coupled receptors, are widely expressed by neural cells, but their roles in the nervous system remain uncertain. In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia. The inflammatory cytokines TNF-alpha and IL-1 beta were also increased in HIV-1-associated dementia brains compared with patients without dementia (p < 0.05), but these same cytokines induced PAR-2 expression on neurons. Enhanced PAR-2 expression and subsequent activation prevented neuronal cell death and induction of the tumor suppressor, p53, caused by the HIV-encoded protein, Tat (P < 0.01). Intrastriatal implantation of a PAR-2 peptide agonist also inhibited Tat-induced neurotoxicity in a mouse model of HIV neuropathogenesis (p < 0.05). Moreover, PAR-2 null animals showed more severe neuroinflammation and neuronal loss caused by Tat neurotoxicity (p < 0.05). TNF-a protected wild-type neurons from Tat-related neurotoxicity, but in PAR-2-deficient neurons, the same concentrations of TNF-alpha were cytotoxic (p < 0.001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death.