A role for CXCL12 (SDF-1α) in the pathogenesis of multiple sclerosis:: Regulation of CXCL12 expression in astrocytes by soluble myelin basic protein
A role for CXCL12 (SDF-1α) in the pathogenesis of multiple sclerosis:: Regulation of CXCL12 expression in astrocytes by soluble myelin basic protein
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DOI：
10.1016/j.jneuroim.2006.05.003
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发表时间：
2006-08-01
影响因子：
3.3
通讯作者：
Berman, Joan W.
中科院分区：
文献类型：
--
作者：
Calderon, Tina M.;Eugenin, Eliseo A.;Berman, Joan W.
导致多发性硬化（MS）的致病机制包括白细胞趋化进入中枢神经系统（CNS）和产生炎性介质，导致少突胶质细胞损伤、脱髓鞘和神经元损伤。因此，调节白细胞进入的因素可能有助于MS的早期事件，以及病变发病机制的后期阶段。CXCL 12（SDF-1 α）是CNS发育中必需的趋化因子，也是静息和活化T细胞以及单核细胞的化学引诱物，在CNS中以低水平组成性表达，并与T细胞和单核细胞基线运输有关。为了确定CXCL 12是否在MS中增加，对慢性活动性和慢性静止性MS的病变进行免疫组织化学分析。在正常人脑切片内血管中的内皮细胞（EC）和脑实质内的少量星形胶质细胞上检测到CXCL 12蛋白。在活动性MS病变中，CXCL 12水平在整个病变区域的星形胶质细胞上以及在血管和血管周围袖口内的一些单核细胞/巨噬细胞上高，EC上染色较少。在静止型MS病变中，CXCL 12染色低于活动型MS病变中观察到的染色，并且在EC和星形胶质细胞上也检测到，特别是在病变边缘附近的肥大星形胶质细胞上。体外实验表明，IL-1 β和髓鞘碱性蛋白（MBP）通过ERK和PI 3-K信号通路诱导星形胶质细胞中的CXCL 12。人脐静脉EC经MBP或IL-1 β处理后不产生CXCL 12。然而，这些EC培养物表达CXCR 4，CXCL 12的受体，表明这种趋化因子可以激活EC产生参与MS的其他介质。一致，发现用CXCL 12处理EC通过PI 3-K和p38依赖性机制上调CCL 2（MCP-1）和CXCL 8（IL-8）。我们的研究结果表明，增加CXCL 12可能会启动和增强MS期间的炎症反应。（c）2006 Elsevier B. V.保留所有权利。
The pathogenic mechanisms that contribute to multiple sclerosis (MS) include leukocyte chemotaxis into the central nervous system (CNS) and the production of inflammatory mediators, resulting in oligodendrocyte damage, demyelination, and neuronal injury. Thus, factors that regulate leukocyte entry may contribute to early events in MS, as well as to later stages of lesion pathogenesis. CXCL12 (SDF-1 alpha), a chemokine essential in CNS development and a chemoattractant for resting and activated T cells, as well as monocytes, is constitutively expressed at low levels in the CNS and has been implicated in T cell and monocyte baseline trafficking. To determine whether CXCL12 is increased in MS, immunohistochemical analyses of lesions of chronic active and chronic silent MS were performed. CXCL12 protein was detected on endothelial cells (EC) in blood vessels within normal human brain sections and on a small number of astrocytes within the brain parenchyma. In active MS lesions, CXCL12 levels were high on astrocytes throughout lesion areas and on some monocytes/macrophages within vessels and perivascular cuffs, with lesser staining on EC. In silent MS lesions, CXCL12 staining was less than that observed in active MS lesions, and also was detected on EC and astrocytes, particularly hypertrophic astrocytes near the lesion edge. Experiments in vitro demonstrated that IL-1 beta and myelin basic protein (MBP) induced CXCL12 in astrocytes by signaling pathways involving ERK and PI3-K. Human umbilical vein-EC did not produce CXCL12 after treatment with MBP or IL-1 beta. However, these EC cultures expressed CXCR4, the receptor for CXCL12, suggesting that this chemokine may activate EC to produce other mediators involved in MS. In agreement, EC treatment with CXCL12 was found to upregulate CCL2 (MCP-1) and CXCL8 (IL-8) by PI3-K and p38-dependent mechanisms. Our findings suggest that increased CXCL12 may initiate and augment the inflammatory response during MS. (c) 2006 Elsevier B.V. All rights reserved.