MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders.
MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders.
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DOI：
10.1016/j.bbi.2017.04.024
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Xing Y;Shepherd N;Lan J;Li W;Rane S;Gupta SK;Zhang S;Dong J;Yu Q
尽管广泛使用联合抗逆转录病毒疗法（cART），但HIV-1相关的神经认知障碍（HAND）仍然是感染人群的主要问题。越来越多的证据表明，基质金属蛋白酶（MMPs）和内源性MMPs组织抑制剂（TIMPs）之间的失衡有助于HAND的发病机制。在我们目前的研究中，我们研究了蛋白质水平和酶活性的基质金属蛋白酶和金属蛋白酶组织抑制剂在血浆和脑脊液（CSF）样本的HIV-1患者有或没有手和HIV-1阴性对照。在HIV-1患者的外周血和CSF中，尤其是HAND患者，MMPs和TIMPs之间存在着不同模式的失衡。在外周血中，与HIV-1阴性对照相比，HIV-1伴或不伴HAND患者的MMP-2、MMP-9、TIMP-1、TIMP-2的蛋白水平以及MMP-2和MMP-9的酶活性均升高。MMP-2的酶活性，但不是MMP-9，进一步增加，在血浆样本的HAND患者比HIV-1患者没有HAND。值得注意的是，血浆中MMP-2/TIMP-2的比率在HAND患者中显著增加，而在没有HAND的患者中没有。CSF中MMP-2活性升高，但MMP-2/TIMP-2比值无明显变化。HAND患者CSF中MMP-9的从头诱导和活化特别突出。血液和CSF中MMPs和TIMPs之间的失衡与这些个体中炎性细胞因子/趋化因子和单核细胞活化的改变有关。此外，来自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渗透性增加和单核细胞/巨噬细胞的稳健迁移。这些结果表明，MMPs和TIMPs之间的失衡参与BBB破坏，并涉及神经系统疾病，如HAND在HIV-1患者的发病机制。
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.
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