Roles of Sema4D-Plexin-B1 Interactions in the Central Nervous System for Pathogenesis of Experimental Autoimmune Encephalomyelitis
Roles of Sema4D-Plexin-B1 Interactions in the Central Nervous System for Pathogenesis of Experimental Autoimmune Encephalomyelitis
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DOI：
10.4049/jimmunol.0903302
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发表时间：
2010-02-01
影响因子：
4.4
通讯作者：
Kumanogoh, Atsushi
中科院分区：
文献类型：
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作者：
Okuno, Tatsusada;Nakatsuji, Yuji;Kumanogoh, Atsushi
虽然信号蛋白最初被认为是神经元发育过程中的轴突引导分子，但越来越多的研究表明，一些信号蛋白在免疫反应的各个阶段都起着至关重要的作用。Sema4D/CD100是一类IV类信号蛋白，已被证明分别通过其受体丛蛋白b1和CD72参与神经系统和免疫系统。然而，Sema4D在神经炎症中的作用仍不清楚。我们发现Sema4D促进了小鼠原代小胶质细胞诱导NO合成酶的表达，在丛蛋白b1缺失的小胶质细胞中这种作用被消除，而在cd72缺失的小胶质细胞中则没有这种作用。此外，在髓鞘少突胶质细胞糖蛋白衍生肽免疫诱导的实验性自身免疫性脑脊髓炎（EAE）的发展过程中，我们观察到Sema4D和plexin-B1分别在浸润的单核细胞和小胶质细胞中被诱导表达。与这些表达谱一致的是，将来自野生型小鼠的髓鞘少突胶质细胞糖蛋白特异性T细胞过继转移到丛蛋白b1缺陷小鼠或丛蛋白b1缺陷CNS常驻细胞的骨髓嵌合体小鼠中，EAE的发展明显减弱。此外，阻断Sema4D抗体可显著抑制EAE发展过程中的神经炎症。总的来说，我们的发现证明了sema4d -丛蛋白b1相互作用在小胶质细胞激活中的作用，并提供了它们在神经炎症中的病理意义。中华免疫学杂志，2010,18(4):1499-1506。
Although semaphorins were-originally identified as axonal guidance molecules during neuronal development, it is emerging that several semaphorins play crucial roles in various phases of immune responses. Sema4D/CD100, a class IV semaphorin, has been shown to be involved in the nervous and immune systems through its receptors plexin-B1 and CD72, respectively. However, the involvement of Sema4D in neuroinflammation still remains unclear. We found that Sema4D promoted inducible NO synthase expression by primary mouse microglia, the effects of which were abolished in plexin-B1-deficient but not in CD72-deficient microglia. In addition, during the development of experimental autoimmune encephalomyelitis (EAE), which was induced by immunization with myelin oligodendrocyte glycoprotein-derived peptides, we observed that the expression of Sema4D and plexin-B1 was induced in infiltrating mononuclear cells and microglia, respectively. Consistent with these expression profiles, when myelin oligodendrocyte glycoprotein-specific T cells derived from wild-type mice were adoptively transferred into plexin-B1-deficient mice or bone marrow chimera mice with plexin-B1-deficient CNS resident cells, the development of EAE was considerably attenuated. Furthermore, blocking Abs against Sema4D significantly inhibited neuroinflammation during EAE development. Collectively, our findings demonstrate the role of Sema4D-plexin-B1 interactions in the activation of microglia and provide their pathologic significance in neuroinflammation. The Journal of Immunology, 2010,184: 1499-1506.