Division of Allergy and Immunology, Research Institute, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
J Neurol Sci. 2013 Nov 15;334(1-2):18-23. doi: 10.1016/j.jns.2013.07.008. Epub 2013 Aug 2.
The tachykinin neuropeptide substance P (SP) has an important signaling role in both the nervous and the immune systems. Two naturally occurring variants of the neurokinin-1 receptor (NK1R) mediate the effects of SP, full-length receptor (NK1R-F) and a truncated form (NK1R-T) that lacks 96 amino acid residues at the C-terminus. We previously reported decreased expression of the NK1R-F in the CNS of HIV-positive individuals in comparison to HIV-negative control subjects. There were no differences in the expression of the NK1R-T in the same groups. In the current study, we quantified the expressions of SP precursor mRNA preprotachykinin (TAC1), NK1R (full and truncated forms), viral load (HIV-gag) and several proinflammatory and immune markers (CD4, CCR5, CXCR4, fractalkine, IL-6, IL-10, CCL2, CCL20 and CD163) in the frontal cortex of autopsied brains from HIV-1-positive individuals with or without HIV-associated neuropathology. The expressions of SP and, to lesser extent, NK1R-F were decreased while the expressions of CXCR4, CCR5 and CCL2 were increased in CNS of individuals with HIV-associated neuropathology. There was no change in HIV loads associated with neuropathology; however, we found a positive correlation between viral loads and the expression of haptoglobin-hemoglobin scavenger receptor CD163. An analysis of CSF from corresponding samples demonstrated an increase in proinflammatory markers (CCL2 MIP-1α and MIP-1β) associated with neuropathology. Although our data confirm the overall inflammatory nature of HIV-associated neuropathology, we observed a decrease in the expression of SP and NK1R-F, which is also associated with other forms of neuroinflammation.
速激肽神经肽物质 P (SP) 在神经系统和免疫系统中都具有重要的信号作用。两种天然存在的神经激肽-1 受体 (NK1R) 变体介导 SP 的作用，全长受体 (NK1R-F) 和缺少 C 末端 96 个氨基酸残基的截断形式 (NK1R-T)。我们之前报道了与 HIV 阴性对照相比，HIV 阳性个体中枢神经系统中 NK1R-F 的表达降低。在同一组中，NK1R-T 的表达没有差异。在当前的研究中，我们定量了 HIV-1 阳性个体尸检大脑前额皮质中 SP 前体 mRNA 前速激肽原 (TAC1)、NK1R（全长和截断形式）、病毒载量（HIV-gag）和几种促炎和免疫标志物（CD4、CCR5、CXCR4、 fractalkine、IL-6、IL-10、CCL2、CCL20 和 CD163）的表达。在伴有或不伴有 HIV 相关神经病理学的个体的中枢神经系统中，SP 的表达减少，而 NK1R-F 的表达减少，CXCR4、CCR5 和 CCL2 的表达增加。与神经病理学相关的病毒载量没有变化；然而，我们发现病毒载量与血红蛋白-血红蛋白清除受体 CD163 的表达呈正相关。对相应样本 CSF 的分析表明，与神经病理学相关的促炎标志物（CCL2 MIP-1α 和 MIP-1β）增加。尽管我们的数据证实了 HIV 相关神经病理学的总体炎症性质，但我们观察到 SP 和 NK1R-F 的表达减少，这也与其他形式的神经炎症有关。
