Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility
Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility
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DOI：
10.1172/jci73408
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发表时间：
2014-06-01
影响因子：
15.9
通讯作者：
Klein, Robyn S.
中科院分区：
文献类型：
--
作者：
Cruz-Orengo, Lillian;Daniels, Brian P.;Klein, Robyn S.
多发性硬化症（MS）是一种以血脑屏障功能障碍为特征的中枢神经系统炎症性疾病，在女性中发病率更高。与其他小鼠品系相比，SJL小鼠品系的EAE可以模拟多发性硬化症的多种特征，包括雌性小鼠对疾病的敏感性增强；然而，疾病易感性的性别和品系依赖性差异背后的分子机制尚未被描述。我们发现鞘氨醇-1-磷酸受体2 （S1PR2）是一种性别和菌株特异性的疾病修饰分子，通过破坏粘附连接来调节血脑屏障的通透性。与男性相比，雌性SJL EAE小鼠和MS女性患者的中枢神经系统疾病易感区S1PR2表达均升高。由于内皮屏障功能增强，药物阻断或缺乏S1PR2信号会降低EAE疾病的严重程度。在体外血脑屏障模型中，S1PR2信号的增强通过激活Rho/ROCK、CDC42和小窝蛋白内噬依赖途径改变了粘附体连接的形成，导致根尖基底极性的丧失和管腔CXCL12向管腔的重新定位。此外，在体内观察到s1pr2依赖性血脑屏障破坏和CXCL12重新定位。这些结果确定了S1PR2信号和血脑屏障极性之间的联系，并暗示S1PR2在中枢神经系统自身免疫期间的性别特异性疾病模式中。
Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity.