Milner Richard, Crocker Stephen J, Hung Stephanie, Wang Xiaoyun, Frausto Ricardo F, del Zoppo Gregory J
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 20550 North Torrey Pines Road, La Jolla, CA 92037, USA.
J Immunol. 2007 Jun 15;178(12):8158-67. doi: 10.4049/jimmunol.178.12.8158.
Early in the pathogenesis of multiple sclerosis, the blood-brain barrier is compromised, which leads to deposition of the plasma proteins fibronectin and vitronectin in cerebral parenchyma. In light of our previous finding that microglial activation in vitro is strongly promoted by fibronectin and vitronectin, we set out to examine the possibility that modulation of microglial activation by fibronectin or vitronectin is an important regulatory mechanism in vivo. In an experimental autoimmune encephalomyelitis mouse model of demyelination, total brain levels of fibronectin and vitronectin were strongly increased and there was a close relationship between fibronectin and vitronectin deposition, microglial activation, and microglial expression of matrix metalloproteinase-9. In murine cell culture, flow cytometry for MHC class I and gelatin zymography revealed that microglial activation and expression of pro-matrix metalloproteinase-9 were significantly increased by fibronectin and vitronectin. Function-blocking studies showed that the influence of fibronectin and vitronectin was mediated by the alpha(5)beta(1) and alpha(v)beta(5) integrins, respectively. Taken together, this work suggests that fibronectin and vitronectin deposition during demyelinating disease is an important influence on microglial activation state. Furthermore, it provides the first evidence that the alpha(5)beta(1) and alpha(v)beta(5) integrins are important mediators of microglial activation.
在多发性硬化症发病早期，血脑屏障受损，导致血浆蛋白纤连蛋白和玻连蛋白沉积于脑实质。鉴于我们之前的发现，即体外小胶质细胞激活受到纤连蛋白和玻连蛋白的强烈促进，我们着手研究纤连蛋白或玻连蛋白对小胶质细胞激活的调节在体内是否是一种重要的调控机制。在脱髓鞘的实验性自身免疫性脑脊髓炎小鼠模型中，纤连蛋白和玻连蛋白的全脑水平显著升高，且纤连蛋白和玻连蛋白沉积、小胶质细胞激活以及基质金属蛋白酶-9的小胶质细胞表达之间存在密切关系。在小鼠细胞培养中，通过MHC I类流式细胞术和明胶酶谱分析发现，纤连蛋白和玻连蛋白可显著增加小胶质细胞激活以及前基质金属蛋白酶-9的表达。功能阻断研究表明，纤连蛋白和玻连蛋白的影响分别由α(5)β(1)和α(v)β(5)整合素介导。综上所述，这项研究表明脱髓鞘疾病期间纤连蛋白和玻连蛋白的沉积对小胶质细胞激活状态有重要影响。此外，它首次证明α(5)β(1)和α(v)β(5)整合素是小胶质细胞激活的重要介质。
