CXCR7 antagonism prevents axonal injury during experimental autoimmune encephalomyelitis as revealed by in vivo axial diffusivity.
CXCR7 antagonism prevents axonal injury during experimental autoimmune encephalomyelitis as revealed by in vivo axial diffusivity.
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DOI：
10.1186/1742-2094-8-170
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发表时间：
2011-12-06
影响因子：
9.3
通讯作者：
Klein RS
中科院分区：
文献类型：
--
作者：
Cruz-Orengo L;Chen YJ;Kim JH;Dorsey D;Song SK;Klein RS
多发性硬化（MS）的特征在于白细胞病理性运输到中枢神经系统（CNS）中。使用小鼠MS模型，实验性自身免疫性脑脊髓炎（EAE），我们以前证明了趋化因子受体CXCR 7的拮抗作用阻断了CXCL 12的内皮细胞隔离，从而增强了表达CXCR 4的白细胞的近腔定位。CXCR 7拮抗作用导致EAE期间白细胞的实质进入减少和正在进行的疾病的改善。值得注意的是，接受高剂量CXCR 7拮抗剂的动物恢复到基线功能，如通过标准临床评分所评估的。由于功能恢复反映轴突的完整性，我们利用扩散张量成像（DTI）来评估轴突损伤CXCR 7拮抗剂与车辆治疗的小鼠从EAE恢复后。C57 BL 6/J小鼠接受MOG反应性Th 1细胞的过继转移，并每天用CXCR 7拮抗剂或载体治疗28天;然后通过DTI评估轴突损伤。成像后，通过用勒克索坚牢蓝（LFB）染色以及髓磷脂碱性蛋白（MBP）和谷胱甘肽S-转移酶-π（GST-π）的免疫荧光对脊髓进行髓鞘和少突胶质细胞的组织学分析。还进行非磷酸化神经丝H（NH-F）的检测以检测损伤的轴突。EAE评分、DTI参数和非磷酸化NH-F免疫荧光的统计学分析通过ANOVA进行，然后进行Bonferroni事后检验。对于所有统计分析，p < 0.05被认为是显著的。在体内DTI地图的脊髓腹外侧白色物质（VLWM）的轴向扩散的幼稚和CXCR 7拮抗剂治疗的小鼠是无法区分的，而溶剂治疗的动物表现出降低的轴向扩散。损伤轴突的定量差异，通过检测非磷酸化NH-F评估，与轴向扩散率测量一致。总体而言，所有给药组中定性髓鞘含量和少突胶质细胞的存在相似，如其径向扩散率值所预期。持续性炎性浸润的定量评估显示，与对照组相比，CXCR 7拮抗剂治疗的小鼠的实质内显著减少。这些数据表明，CXCR 7拮抗作用不仅可以预防持续性炎症，还可以保护轴突完整性。因此，靶向CXCR 7改变了EAE期间的疾病严重程度和恢复，表明该分子在疾病的两个阶段中的作用。
Multiple Sclerosis (MS) is characterized by the pathological trafficking of leukocytes into the central nervous system (CNS). Using the murine MS model, experimental autoimmune encephalomyelitis (EAE), we previously demonstrated that antagonism of the chemokine receptor CXCR7 blocks endothelial cell sequestration of CXCL12, thereby enhancing the abluminal localization of CXCR4-expressing leukocytes. CXCR7 antagonism led to decreased parenchymal entry of leukocytes and amelioration of ongoing disease during EAE. Of note, animals that received high doses of CXCR7 antagonist recovered to baseline function, as assessed by standard clinical scoring. Because functional recovery reflects axonal integrity, we utilized diffusion tensor imaging (DTI) to evaluate axonal injury in CXCR7 antagonist- versus vehicle-treated mice after recovery from EAE. C57BL6/J mice underwent adoptive transfer of MOG-reactive Th1 cells and were treated daily with either CXCR7 antagonist or vehicle for 28 days; and then evaluated by DTI to assess for axonal injury. After imaging, spinal cords underwent histological analysis of myelin and oligodendrocytes via staining with luxol fast blue (LFB), and immunofluorescence for myelin basic protein (MBP) and glutathione S-transferase-π (GST-π). Detection of non-phosphorylated neurofilament H (NH-F) was also performed to detect injured axons. Statistical analysis for EAE scores, DTI parameters and non-phosphorylated NH-F immunofluorescence were done by ANOVA followed by Bonferroni post-hoc test. For all statistical analysis a p < 0.05 was considered significant. In vivo DTI maps of spinal cord ventrolateral white matter (VLWM) axial diffusivities of naïve and CXCR7 antagonist-treated mice were indistinguishable, while vehicle-treated animals exhibited decreased axial diffusivities. Quantitative differences in injured axons, as assessed via detection of non-phosphorylated NH-F, were consistent with axial diffusivity measurements. Overall, qualitative myelin content and presence of oligodendrocytes were similar in all treatment groups, as expected by their radial diffusivity values. Quantitative assessment of persistent inflammatory infiltrates revealed significant decreases within the parenchyma of CXCR7 antagonist-treated mice versus controls. These data suggest that CXCR7 antagonism not only prevents persistent inflammation but also preserves axonal integrity. Thus, targeting CXCR7 modifies both disease severity and recovery during EAE, suggesting a role for this molecule in both phases of disease.
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DOI：
10.1084/jem.20102010
发表时间：
2011-02-14
期刊：
The Journal of experimental medicine
影响因子：
--
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
通讯作者：
Klein RS
影响因子：
--
作者：
Haines, Jeffery D.;Inglese, Matilde;Casaccia, Patrizia
通讯作者：
Casaccia, Patrizia
影响因子：
9.3
作者：
Jackson SJ;Giovannoni G;Baker D
通讯作者：
Baker D
影响因子：
11.2
作者：
Goettle, Peter;Kremer, David;Kuery, Patrick
通讯作者：
Kuery, Patrick
影响因子：
5.4
作者：
Dandekar, AA;Wu, CF;Perlman, S
通讯作者：
Perlman, S