Department of Neurology, The Affiliated Sanming First Hospital of Fujian Medical University, Sanming 365000, Fujian, China.
Mol Immunol. 2013 Jan;53(1-2):43-51. doi: 10.1016/j.molimm.2012.06.009. Epub 2012 Jul 13.
Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is a T cell-mediated autoimmune condition characterized by prominent inflammation in the CNS. In this model, autoreactive T cells are primed in peripheral lymph nodes and migrate into uninflamed CNS across blood-cerebrospinal fluid barrier (BCSFB) and blood-brain barrier (BBB) to initiate inflammation. However, the molecular mechanism controlling T cell migration remains to be determined. In an in vivo EAE mouse model, we have shown that Irgm1 (also known as LRG-47), a member of the immunity-related GTPase family, promotes the disruption of both BCSFB and BBB, and exacerbates the phenotypes of MOG-induced EAE. During EAE, Irgm1 was up-regulated in reactive astrocytes, ependymal cells and epithelial cells of the choroids plexus, which, in turn, promotes T cell infiltration into the CNS. Electron microscopy study showed that the MOG-induced disruption of both BBB and BCSFB was protected in the Irgm1(-/-) mice. Moreover, the expression of Claudin-5 (CLN-5), a major molecular determinant of BBB, in brain microvessel endothelial cells (BMVECs) was decreased in WT EAE mice while increased in Irgm1(-/-) mice. In addition, the expression of CC-chemokine ligand 20 (CCL-20), an important chemokine mediating lymphocyte trafficking across BCSFB, in the epithelial cells of choroids plexus was significantly suppressed in naïve and EAE-induced Irgm1(-/-) mice. These data suggest that Irgm1 is an important molecular regulator for the properties of both BBB and BCSFB, and a proinflammatory factor for EAE.
实验性自身免疫性脑脊髓炎（EAE），多发性硬化症（MS）的动物模型，是一种以中枢神经系统（CNS）中明显炎症为特征的 T 细胞介导的自身免疫性疾病。在该模型中，自身反应性 T 细胞在外周淋巴结中被激活，并穿过血脑屏障（BBB）和血脑脊液屏障（BCSFB）迁移到未发炎的 CNS 中，从而引发炎症。然而，控制 T 细胞迁移的分子机制仍有待确定。在体内 EAE 小鼠模型中，我们已经表明，免疫相关 GTPase 家族的成员 Irgm1（也称为 LRG-47）促进了 BCSFB 和 BBB 的破坏，并加重了 MOG 诱导的 EAE 的表型。在 EAE 期间，反应性星形胶质细胞、室管膜细胞和脉络丛上皮细胞中 Irgm1 上调，这反过来又促进了 T 细胞浸润到 CNS 中。电子显微镜研究表明，在 Irgm1（-/-）小鼠中，MOG 诱导的 BBB 和 BCSFB 的破坏得到了保护。此外，在 WT EAE 小鼠中，脑微血管内皮细胞（BMVECs）中 Claudin-5（CLN-5）的表达减少，而在 Irgm1（-/-）小鼠中增加。此外，在 naïve 和 EAE 诱导的 Irgm1（-/-）小鼠中，脉络丛上皮细胞中 CC 趋化因子配体 20（CCL-20）的表达显著受到抑制，CCL-20 是一种重要的趋化因子，介导淋巴细胞穿过 BCSFB 的迁移。这些数据表明，Irgm1 是 BBB 和 BCSFB 特性的重要分子调节剂，也是 EAE 的促炎因子。
