Decreased TNF Levels and Improved Retinal Ganglion Cell Survival in MMP-2 Null Mice Suggest a Role for MMP-2 as TNF Sheddase.
Decreased TNF Levels and Improved Retinal Ganglion Cell Survival in MMP-2 Null Mice Suggest a Role for MMP-2 as TNF Sheddase.
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DOI：
10.1155/2015/108617
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发表时间：
2015
影响因子：
4.6
通讯作者：
Moons L
中科院分区：
文献类型：
--
作者：
De Groef L;Salinas-Navarro M;Van Imschoot G;Libert C;Vandenbroucke RE;Moons L
基质金属蛋白酶（MMPs）在中枢神经系统（CNS）中既是朋友又是敌人：虽然参与许多神经退行性疾病和神经炎性疾病，但它们的作用似乎是健康CNS不可或缺的。因此，CNS中的病理状况通常与MMP活性不平衡和复杂MMP依赖性蛋白酶网络的紊乱有关。同样，在视网膜中，动物模型和人类患者的各种研究表明MMP参与青光眼。在这项研究中，我们试图确定MMP-2在兴奋性视网膜的时空表达谱，并阐明其在青光眼发病机制中的作用。我们发现，玻璃体内注射NMDA诱导MMP-2的表达上调的Müller神经胶质细胞。此外，MMP-2基因敲除小鼠在对视网膜的兴奋性毒性损伤后显示出减弱的视网膜神经节细胞死亡，这伴随着正常的神经胶质反应性，但TNF水平降低。因此，我们提出了一种新的MMP-2在体内的功能，作为一种激活脱落的肿瘤坏死因子（TNF）。鉴于TNF作为促炎细胞因子和神经退行性变加剧介质的关键作用，这些发现为促进青光眼神经退行性变的病理过程以及中枢神经系统中神经炎症和神经退行性变的相互作用提供了重要的新见解。
Matrix metalloproteinases (MMPs) have been designated as both friend and foe in the central nervous system (CNS): while being involved in many neurodegenerative and neuroinflammatory diseases, their actions appear to be indispensable to a healthy CNS. Pathological conditions in the CNS are therefore often related to imbalanced MMP activities and disturbances of the complex MMP-dependent protease network. Likewise, in the retina, various studies in animal models and human patients suggested MMPs to be involved in glaucoma. In this study, we sought to determine the spatiotemporal expression profile of MMP-2 in the excitotoxic retina and to unravel its role during glaucoma pathogenesis. We reveal that intravitreal NMDA injection induces MMP-2 expression to be upregulated in the Müller glia. Moreover, MMP-2 null mice display attenuated retinal ganglion cell death upon excitotoxic insult to the retina, which is accompanied by normal glial reactivity, yet reduced TNF levels. Hence, we propose a novel in vivo function for MMP-2, as an activating sheddase of tumor necrosis factor (TNF). Given the pivotal role of TNF as a proinflammatory cytokine and neurodegeneration-exacerbating mediator, these findings generate important novel insights into the pathological processes contributing to glaucomatous neurodegeneration and into the interplay of neuroinflammation and neurodegeneration in the CNS.