Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis
Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis
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DOI：
10.1093/brain/awg285
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发表时间：
2003-12-01
期刊：
影响因子：
14.5
通讯作者：
Yong, VW
中科院分区：
文献类型：
--
作者：
Bar-Or, A;Nuttall, RK;Yong, VW
基质金属蛋白酶（MMPs）与多发性硬化症有关，其作用之一可能是促进循环白细胞向中枢神经系统的转运。研究只关注少数mmmp，并且对于23个MMP家族成员中哪些对多发性硬化症过程至关重要仍不清楚。使用定量实时聚合酶链反应，我们系统地分析了从正常人血液中分离的白细胞亚群中所有23个MMP成员的表达。我们发现MMP在不同的细胞群体中有独特的表达模式：MMP-11、MMP-26和MMP-27在B细胞中富集，而MMP-15、MMP-16、MMP-24和MMP-28在T淋巴细胞中富集。令人感兴趣的是，大多数MMP成员在单核细胞中富集：MMP-1、MMP-3、MMP-9、MMP-10、MMP-14、MMP-19和MMP-25。MMP-2和MMP-17在单核细胞中也有显著的表达，尽管B细胞中也有大量的这些MMPs。与许多MMP成员的强表达相对应，单核细胞在培养血脑屏障模型中的迁移速度比T淋巴细胞或B淋巴细胞更快。最后，我们发现与正常人相比，多发性硬化症患者中两种单核细胞表达的MMPs水平更高：MMP-2和MMP-14。组织金属蛋白酶抑制剂(TIMP)-2在多发性硬化症患者的单核细胞中也升高，这为MMP-14和TIMP-2激活MMP-2提供了一种机制。这些结果强调单核细胞是多发性硬化症中神经炎症的重要贡献者，其机制涉及它们的高MMP表达，并且它们识别特定的MMP成员作为该疾病新疗法的靶点。
Matrix metalloproteinases (MMPs) are implicated in multiple sclerosis where one of their roles may be to facilitate the transmigration of circulating leukocytes into the CNS. Studies have focused on only a few MMPs, and much remains unknown of which of the 23 MMP family members is/are critical to the multiple sclerosis disease process. Using quantitative real time polymerase chain reactions, we have systematically analysed the expression of all 23 MMP members in subsets of leukocytes isolated from the blood of normal individuals. We found a distinctive pattern of MMP expression in different cellular populations: MMP-11, MMP-26 and MMP-27 were enriched in B cells, while MMP-15, MMP-16, MMP-24 and MMP-28 were prominent in T lymphocytes. Of interest is the enrichment of a majority of MMP members in monocytes: MMP-1, MMP-3, MMP-9, MMP-10, MMP-14, MMP-19 and MMP-25. MMP-2 and MMP-17 were also significantly represented in monocytes, although B cells had significant amounts of these MMPs. In correspondence with their strong expression of many MMP members, monocytes migrated more rapidly across a model of the blood-brain barrier in culture than T or B lymphocytes. Finally, we found higher levels of two of the monocyte-expressed MMPs in multiple sclerosis patients compared with normal individuals: MMP-2 and MMP-14. Tissue inhibitor of metalloproteinases (TIMP)-2 was also elevated in monocytes from multiple sclerosis patients, providing a mechanism for the reported activation of MMP-2 by MMP-14 and TIMP-2. These results emphasize that monocytes are prominent contributors of the neuroinflammation in multiple sclerosis through a mechanism that involves their high MMP expression and that they identify specific MMP members as targets for novel therapeutics in the disease.