CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity.
CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity.
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DOI：
10.1084/jem.20102010
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发表时间：
2011-02-14
期刊：
影响因子：
--
通讯作者：
Klein RS
中科院分区：
文献类型：
--
作者：
Cruz-Orengo L;Holman DW;Dorsey D;Zhou L;Zhang P;Wright M;McCandless EE;Patel JR;Luker GD;Littman DR;Russell JH;Klein RS
在中枢神经系统自身免疫过程中，脑内皮细胞CXCR7从血管周围空间内化CXCL12，从而允许白细胞迁移到中枢神经系统实质。在多发性硬化症（MS）病变中，血脑屏障腹腔表面的一种白细胞定位线索CXCL12丢失。然而，体内CXCL12丰度降低的机制和后果尚不清楚。本研究表明，在实验性自身免疫性脑脊髓炎（EAE）期间，清除CXCL12的CXCR7的激活对于白细胞通过内皮屏障进入中枢神经系统（CNS）实质至关重要，这是ms的一种模型，在EAE期间，炎症浸润部位内皮屏障上CXCR7的表达增加。使用CXCR7拮抗剂治疗可改善EAE，减少白细胞浸润到中枢神经系统实质和实质VCAM-1表达，并增加CXCL12的腹腔水平。体外培养的原代脑内皮细胞中，白细胞介素17和白细胞介素1β升高，干扰素γ降低，CXCR7表达升高，CXCL12内化。这些发现确定了白细胞经血管进入中枢神经系统的分子需求，并提示CXCR7阻断可能对治疗多发性硬化症具有治疗作用。
During CNS autoimmunity, brain endothelial cell CXCR7 internalizes CXCL12 from the perivascular space, thereby permitting leukocyte migration into the CNS parenchyma. Loss of CXCL12, a leukocyte localizing cue, from abluminal surfaces of the blood–brain barrier occurs in multiple sclerosis (MS) lesions. However, the mechanisms and consequences of reduced abluminal CXCL12 abundance remain unclear. Here, we show that activation of CXCR7, which scavenges CXCL12, is essential for leukocyte entry via endothelial barriers into the central nervous system (CNS) parenchyma during experimental autoimmune encephalomyelitis (EAE), a model for MS. CXCR7 expression on endothelial barriers increased during EAE at sites of inflammatory infiltration. Treatment with a CXCR7 antagonist ameliorated EAE, reduced leukocyte infiltration into the CNS parenchyma and parenchymal VCAM-1 expression, and increased abluminal levels of CXCL12. Interleukin 17 and interleukin 1β increased, whereas interferon-γ decreased, CXCR7 expression on and CXCL12 internalization in primary brain endothelial cells in vitro. These findings identify molecular requirements for the transvascular entry of leukocytes into the CNS and suggest that CXCR7 blockade may have therapeutic utility for the treatment of MS.
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影响因子：
6
作者：
McCandless, Erin E.;Piccio, Laura;Klein, Robyn S.
通讯作者：
Klein, Robyn S.
影响因子：
4.8
作者：
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Kuhlmann, Christoph R. W.
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4.4
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通讯作者：
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5.4
作者：
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通讯作者：
Diamond, MS