Extracellular matrix metalloproteinase inducer shows active perivascular cuffs in multiple sclerosis
Extracellular matrix metalloproteinase inducer shows active perivascular cuffs in multiple sclerosis
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DOI：
10.1093/brain/awt093
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发表时间：
2013-06-01
期刊：
影响因子：
14.5
通讯作者：
Yong, V. Wee
中科院分区：
文献类型：
--
作者：
Agrawal, Smriti M.;Williamson, Jacqueline;Yong, V. Wee
炎症性血管周围袖带由白细胞组成，白细胞在浸润到中枢神经系统实质之前积聚在毛细血管后小静脉周围的血管周围空间中。炎症性血管周围袖带常见于多发性硬化症患者的中枢神经系统和实验性自身免疫性脑脊髓炎动物模型中。聚集在血管周围空间的白细胞分泌基质金属蛋白酶，帮助它们迁移到神经实质中。我们先前描述了基质金属蛋白酶表达的上游诱导物，细胞外基质金属蛋白酶诱导物（CD 147），在实验性自身免疫性脑脊髓炎中升高，并且其抑制减少了白细胞进入中枢神经系统。在这里，我们研究了细胞外基质金属蛋白酶诱导剂的表达是否随小鼠实验性自身免疫性脑脊髓炎病变的时间演变而变化，它是否在多发性硬化标本中均匀上调，以及它是否是多发性硬化病变中炎性血管周围袖口的一个特征。在实验性自身免疫性脑脊髓炎中，细胞外基质金属蛋白酶诱导因子的升高与疾病临床体征的出现和持续相关。在小鼠和人类样本中，在健康和疾病状态下的内皮细胞上检测到细胞外基质金属蛋白酶诱导剂，但在白细胞上的炎性血管周围袖口中和周围显著增加，与基质金属蛋白酶表达相关，并且在包括小胶质细胞在内的驻留细胞上。多发性硬化病变中表达细胞外基质金属蛋白酶诱导因子的白细胞群包括CD 4+和CD 8 + T淋巴细胞、B淋巴细胞和单核细胞/巨噬细胞。细胞外基质金属蛋白酶诱导因子的内皮外表达是多发性硬化病变活动的标志物，存在于含白细胞的血管周围袖口，但不存在于非活动性病变中。通过使用功能阻断抗体，我们牵连的细胞外基质金属蛋白酶诱导剂在白细胞粘附内皮细胞，并确定其活性是更重要的白细胞比内皮细胞在白细胞-内皮细胞在体外接合。细胞外基质金属蛋白酶诱导剂活性通过与核因子κ B信号传导相关的机制调节白细胞上α 4整合素的水平。阻断细胞外基质金属蛋白酶诱导剂可减弱单核细胞和B淋巴细胞穿过培养的血脑屏障模型的迁移。总之，我们描述了突出的细胞外基质金属蛋白酶诱导剂在中枢神经系统炎性血管周围袖口，强调其在基质金属蛋白酶诱导和白细胞粘附的双重作用，并强调细胞外基质金属蛋白酶诱导剂的升高作为一个协调者的白细胞浸润到中枢神经系统实质。
Inflammatory perivascular cuffs are comprised of leucocytes that accumulate in the perivascular space around post-capillary venules before their infiltration into the parenchyma of the central nervous system. Inflammatory perivascular cuffs are commonly found in the central nervous system of patients with multiple sclerosis and in the animal model experimental autoimmune encephalomyelitis. Leucocytes that accumulate in the perivascular space secrete matrix metalloproteinases that aid their transmigration into the neural parenchyma. We described previously that the upstream inducer of matrix metalloproteinase expression, extracellular matrix metalloproteinase inducer (CD147), was elevated in experimental autoimmune encephalomyelitis, and that its inhibition reduced leucocyte entry into the central nervous system. Here we investigated whether the expression of extracellular matrix metalloproteinase inducer varies with the temporal evolution of lesions in murine experimental autoimmune encephalomyelitis, whether it was uniformly upregulated across multiple sclerosis specimens, and whether it was a feature of inflammatory perivascular cuffs in multiple sclerosis lesions. In experimental autoimmune encephalomyelitis, elevation of extracellular matrix metalloproteinase inducer was correlated with the appearance and persistence of clinical signs of disease. In both murine and human samples, extracellular matrix metalloproteinase inducer was detected on endothelium in healthy and disease states but was dramatically increased in and around inflammatory perivascular cuffs on leucocytes, associated with matrix metalloproteinase expression, and on resident cells including microglia. Leucocyte populations that express extracellular matrix metalloproteinase inducer in multiple sclerosis lesions included CD4+ and CD8+ T lymphocytes, B lymphocytes and monocyte/macrophages. The extra-endothelial expression of extracellular matrix metalloproteinase inducer was a marker of the activity of lesions in multiple sclerosis, being present on leucocyte-containing perivascular cuffs but not in inactive lesions. By using a function-blocking antibody, we implicate extracellular matrix metalloproteinase inducer in the adhesion of leucocytes to endothelial cells and determined that its activity was more crucial on leucocytes than on endothelium in leucocyte-endothelial cell engagement in vitro. Extracellular matrix metalloproteinase inducer activity regulated the level of alpha 4 integrin on leucocytes through a mechanism associated with nuclear factor kappa B signalling. Blocking extracellular matrix metalloproteinase inducer attenuated the transmigration of monocytes and B lymphocytes across a model of the blood-brain barrier in culture. In summary, we describe the prominence of extracellular matrix metalloproteinase inducer in central nervous system inflammatory perivascular cuffs, emphasize its dual role in matrix metalloproteinase induction and leucocyte adhesion, and highlight the elevation of extracellular matrix metalloproteinase inducer as an orchestrator of the infiltration of leucocytes into the central nervous system parenchyma.