Xing Yanyan, Shepherd Nicole, Lan Jie, Li Wei, Rane Sushmita, Gupta Samir K, Zhang Shanxiang, Dong Jun, Yu Qigui
Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong 510632, China; Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
Indiana Center for AIDS Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
Brain Behav Immun. 2017 Oct;65:161-172. doi: 10.1016/j.bbi.2017.04.024. Epub 2017 May 6.
HIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of combined antiretroviral therapy (cART). Growing evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) contributes to the pathogenesis of HAND. In our present study, we examined protein levels and enzymatic activities of MMPs and TIMPs in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients with or without HAND and HIV-1-negative controls. Imbalances between MMPs and TIMPs with distinct patterns were revealed in both the peripheral blood and CSF of HIV-1 patients, especially those with HAND. In the peripheral blood, the protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and the enzymatic activities of MMP-2 and MMP-9 were increased in HIV-1 patients with or without HAND when compared with HIV-1-negative controls. The enzymatic activity of MMP-2, but not MMP-9, was further increased in plasma samples of HAND patients than that of HIV-1 patients without HAND. Notably, the ratio of MMP-2/TIMP-2 in plasma was significantly increased in HAND patients, not in patients without HAND. In the CSF, MMP-2 activity was increased, but the ratio of MMP-2/TIMP-2 was not altered. De novo induction and activation of MMP-9 in the CSF of HAND patients was particularly prominent. The imbalances between MMPs and TIMPs in the blood and CSF were related to the altered profiles of inflammatory cytokines/chemokines and monocyte activation in these individuals. In addition, plasma from HIV-1 patients directly induced integrity disruption of an in vitro blood-brain barrier (BBB) model, leading to increased BBB permeability and robust transmigration of monocytes/macrophages. These results indicate that imbalances between MMPs and TIMPs are involved in BBB disruption and are implicated in the pathogenesis of neurological disorders such as HAND in HIV-1 patients.
尽管联合抗逆转录病毒疗法（cART）已广泛应用，但HIV-1相关神经认知障碍（HAND）仍是感染人群中的一个主要问题。越来越多的证据表明，基质金属蛋白酶（MMPs）与内源性MMP组织抑制剂（TIMPs）之间的失衡促成了HAND的发病机制。在我们目前的研究中，我们检测了伴有或不伴有HAND的HIV-1患者以及HIV-1阴性对照者的血浆和脑脊液（CSF）样本中MMPs和TIMPs的蛋白水平及酶活性。在HIV-1患者的外周血和脑脊液中均发现了MMPs与TIMPs之间存在不同模式的失衡，尤其是那些患有HAND的患者。在外周血中，与HIV-1阴性对照者相比，伴有或不伴有HAND的HIV-1患者的MMP-2、MMP-9、TIMP-1、TIMP-2蛋白水平以及MMP-2和MMP-9的酶活性均升高。HAND患者血浆样本中MMP-2的酶活性进一步升高，而MMP-9未升高。值得注意的是，HAND患者血浆中MMP-2/TIMP-2的比值显著升高，而无HAND的患者则未升高。在脑脊液中，MMP-2活性升高，但MMP-2/TIMP-2的比值未改变。HAND患者脑脊液中MMP-9的从头诱导和激活尤为显著。血液和脑脊液中MMPs与TIMPs之间的失衡与这些个体中炎性细胞因子/趋化因子谱的改变以及单核细胞活化有关。此外，HIV-1患者的血浆直接诱导体外血脑屏障（BBB）模型的完整性破坏，导致BBB通透性增加以及单核细胞/巨噬细胞的大量迁移。这些结果表明，MMPs与TIMPs之间的失衡参与了BBB破坏，并与HIV-1患者中诸如HAND等神经疾病的发病机制有关。
