EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis
EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis
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DOI：
10.1523/jneurosci.3659-10.2011
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发表时间：
2011-01-12
影响因子：
5.3
通讯作者：
Yong, V. Wee
中科院分区：
文献类型：
--
作者：
Agrawal, Smriti M.;Silva, Claudia;Yong, V. Wee
细胞外基质金属蛋白酶诱导因子（extracellular matrix metalloproteinase inducer，EMMPRIN，CD 147）是IG超家族成员，具有多种生理功能，包括诱导基质金属蛋白酶（matrix metalloproteinases，MMPs）、白细胞活化和肿瘤进展。在这项研究中，我们说明了一种新的参与EMMPRIN多发性硬化症（MS）及其动物模型，实验性自身免疫性脑脊髓炎（EAE）。我们发现EMMPRIN水平上调外周血白细胞发病前EAE的临床症状和浸润性白细胞和驻留细胞内的CNS有症状的小鼠。在EAE脑切片中，EMMPRIN表达定位于MMP-9蛋白和活性。EMMPRIN水平的增加也是MS受试者脑样本的特征，特别是在含斑块的区域。为了评估EMMPRIN水平升高的影响，我们用EMMPRIN功能阻断抗体治疗EAE小鼠，发现EAE临床严重程度降低，伴有CNS实质白细胞浸润减少。抗EMMPRIN抗体对EAE临床体征的改善主要依赖于临床体征发作期间的给药，这通常与白细胞大量流入CNS相关。此外，抗EMMPRIN治疗小鼠的疾病严重程度降低与胶质界膜MMP蛋白水解活性降低相关，胶质界膜是白细胞实质浸润前的最后屏障。总之，我们的研究结果是第一个强调EMMPRIN在MS和EAE中的作用，EMMPRIN通过增加MMP活性调节白细胞运输。这些结果将EMMPRIN确定为MS的新治疗靶点。
Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a member of the Ig superfamily, with various physiological roles including the induction of matrix metalloproteinases (MMPs), leukocyte activation, and tumor progression. In this study, we illustrate a novel involvement of EMMPRIN in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). We found EMMPRIN levels to be upregulated on peripheral leukocytes before onset of EAE clinical signs and on infiltrating leukocytes and resident cells within the CNS in symptomatic mice. In EAE brain sections, EMMPRIN expression was localized with MMP-9 protein and activity. The increased EMMPRIN level was also characteristic of brain samples from MS subjects, particularly in plaque-containing areas. To evaluate the implications of elevated EMMPRIN levels, we treated EAE mice with an EMMPRIN function-blocking antibody and found reduced EAE clinical severity accompanied by decreased CNS parenchymal infiltration of leukocytes. Amelioration of EAE clinical signs by the anti-EMMPRIN antibody was critically dependent on its administration around the period of onset of clinical signs, which is typically associated with significant influx of leukocytes into the CNS. Moreover, the reduction in disease severity in anti-EMMPRIN treated mice was associated with diminished MMP proteolytic activity at the glia limitans, the final barrier before parenchymal infiltration of leukocytes. Together, our results are the first to emphasize a role for EMMPRIN in MS and EAE, whereby EMMPRIN regulates leukocyte trafficking through increasing MMP activity. These results identify EMMPRIN as a novel therapeutic target in MS.