Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation
Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation
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DOI：
10.1016/j.nbd.2006.02.006
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发表时间：
2006-07-01
影响因子：
6.1
通讯作者：
Rosenberg, Gary A.
中科院分区：
文献类型：
--
作者：
Gurney, Kate J.;Estrada, Eduardo Y.;Rosenberg, Gary A.
在神经炎症中，血脑屏障（BBB）开放是由基质金属蛋白酶（MMPs）介导的。我们使用MMP-3敲除（KO）小鼠和脂多糖（LPS）诱导的血脑屏障开放来检验MMP-3在血脑屏障损伤中起作用的假设。我们发现MMP-3基因敲除小鼠脑内注射LPS后血脑屏障的破坏程度低于野生型小鼠（P < 0.0006）。MMP-3 KO小鼠的MMP-9比WT小鼠少，但活化水平相似。此外，MMP-9 mRNA水平在MMP 3 KO和WT中均增加至相似水平，表明内源性和外源性来源。无偏体视学显示，与KO小鼠相比，MMP-3 WT小鼠脑中的中性粒细胞计数增加。紧密连接蛋白，claudin-5和occludin，以及基底层蛋白，层粘连蛋白-α 1的降解，在KO中受到的影响小于WT。我们的研究结果提供了第一个体内证据，MMP-3攻击基底层和紧密连接蛋白，打开血脑屏障，从而促进中性粒细胞流入。(c)2006年爱思唯尔公司All rights reserved.
Blood-brain barrier (BBB) opening is mediated by matrix metalloproteinases (MMPs) in neuroinflammation. We tested the hypothesis that MMP-3 plays a role in BBB damage, using MMP-3 knockout (KO) mice and lipopolysaccharide (LPS)-induced opening of the BBB. We found less disruption of the BBB after intracerebral LPS injection in MMP-3 KO mice than in wild type (P < 0.0006). MMP-3 KO mice had less MMP-9 than WT mice but similar levels of activation. Moreover, MMP-9 mRNA levels were increased to a similar level in both the MMP3 KO and WT, suggesting both endogenous and exogenous sources. Unbiased stereology showed increased neutrophil counts in the brains of MMP-3 WT compared to KO mice. Degradation of tight junction proteins, claudin-5 and occludin, and the basal lamina protein, laminin-alpha 1, was less affected in the KO than in the WT. Our results provide the first in vivo evidence that MMP-3 attacks the basal lamina and tight junction proteins, opening the BBB, thereby facilitating neutrophil influx. (c) 2006 Elsevier Inc. All rights reserved.