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Critical role of KLK6 in the pathogenesis of Multiple Sclerosis

KLK6 在多发性硬化症发病机制中的关键作用

基本信息

批准号：
23700436
负责人：
BANDO Yoshio
金额：
$ 2.41万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23700436/
关键词：
多発性硬化症セリンプロテアーゼオリゴデンドロサイト脱髄 EAE

项目摘要

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). It results in neurological impairments. One of animal model is myelin oligodendrocyte glycoprotein (MOG)- induced experimental autoimmune encephalomyelitis (EAE), which is characterized by paralysis and immune cell infiltration in the CNS. We have previously reported that a serine protease, Kallikrein 6 (KLK6), is produced by exclusively mature oligodendrocytes in the CNS, and that KLK6 is up-regulated in oligodendrocytes after spinal cord injury and EAE. However, the function of KLK6 in the pathogenesis of MS has not been fully understood.Here we report that KLK6 is involved in onset of EAE via BBB breakdown. To investigate the role of KLK6 in demyelination, we examined the effect of KLK6 on onset of EAE in KLK6 knock out (KO) mice. KLK6 KO mice exhibited an altered EAE progression characterized by delayed onset and progression of clinical symptoms as compared to wild-type mice. Histological study with luxol fast blue also revealed a decreased number of infiltrating inflammatory cells in spinal cord with EAE, suggesting that absence of KLK6 suppressed infiltration of peripheral inflammatory cells into the CNS with EAE. We next examined the effect of KLK6 on BBB permeability by evans blue dye injection. KLK6 KO mice showed much suppression of BBB permeability compared to wild-type mice. Finally we found that activation of Matrix metalloprotease-9 was inhibited in KLK6 KO mice with EAE. These results suggest that KLK6 play a crucial role of the pathogenesis of EAE.

多发性硬化（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病。会导致神经损伤。髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎（EAE）是一种以中枢神经系统瘫痪和免疫细胞浸润为特征的动物模型。我们以前曾报道，丝氨酸蛋白酶，激肽释放酶6（KLK 6），是专门由成熟的少突胶质细胞在中枢神经系统中，和KLK 6的上调少突胶质细胞脊髓损伤和EAE后。然而，KLK 6在MS发病机制中的作用尚未完全了解，本文报道KLK 6通过破坏BBB参与EAE的发病。为了研究KLK 6在脱髓鞘中的作用，我们在KLK 6敲除（KO）小鼠中检测了KLK 6对EAE发作的影响。与野生型小鼠相比，KLK 6 KO小鼠表现出改变的EAE进展，其特征在于临床症状的延迟发作和进展。用luxol坚牢蓝进行的组织学研究也揭示了EAE脊髓中浸润炎性细胞的数量减少，表明KLK 6的缺乏抑制了EAE外周炎性细胞向CNS的浸润。我们接下来通过伊文思蓝染料注射检测KLK 6对BBB通透性的影响。与野生型小鼠相比，KLK 6 KO小鼠表现出对BBB渗透性的极大抑制。最后，我们发现基质金属蛋白酶-9的激活在EAE的KLK 6 KO小鼠中被抑制。提示KLK 6在EAE的发病机制中起重要作用。