Kallikrein 6 secreted by oligodendrocytes regulates the progression of experimental autoimmune encephalomyelitis
Kallikrein 6 secreted by oligodendrocytes regulates the progression of experimental autoimmune encephalomyelitis
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DOI：
10.1002/glia.23249
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发表时间：
2018-02-01
期刊：
影响因子：
6.2
通讯作者：
Yoshida, Shigetaka
中科院分区：
文献类型：
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作者：
Bando, Yoshio;Hagiwara, Yoshiaki;Yoshida, Shigetaka
多发性硬化症(MS)是一种中枢神经系统(CNS)炎性脱髓鞘疾病，实验性自身免疫性脑脊髓炎(EAE)是一种成熟的动物模型。在这里，我们利用KLK6基因敲除(KLK6-/-)小鼠检测了KLK6(一种由少突胶质细胞产生的丝氨酸蛋白酶)在EAE中的病理生理学作用。与KLK6+/+(野生型)小鼠相比，KLK6-/-小鼠表现出较轻的EAE症状，包括发病延迟和轻度瘫痪。KLK6的缺失通过降低血脑屏障(BBB)通透性，降低炎性细胞因子、趋化因子及其受体的表达水平，抑制基质金属蛋白酶-9的表达，减少外周炎性细胞向中枢神经系统的渗透。扫描电子显微镜分析显示，在EAE进展的早期阶段(3-7天)，KLK6+/+小鼠的脱髓鞘特征是髓鞘从轴突脱离，而KLK6-/-小鼠则没有。有趣的是，在MOG免疫后第3天，脑脊液和脊髓中也检测到了抗MOG自身抗体。此外，用抗MOG自身抗体处理原代培养的OL可引起少突胶质细胞的形态改变，髓鞘碱性蛋白和KLK6的表达增加。我们还建立了一种新的检测人脑脊液中活性KLK6的酶联免疫吸附分析方法。在人类尸检大脑样本中，使用一种特异性识别蛋白质的激活形式的抗体，在OL中检测到活性KLK6的表达。综上所述，我们的研究结果表明，OLS分泌的KLK6在EAE/MS的发病机制中起着关键作用，可能成为治疗MS的潜在靶点。
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of the disease. Here, we examined the pathophysiological role of Kallikrein 6 (Klk6), a serine protease produced by oligodendrocytes (OLs), in EAE using Klk6 knockout (Klk6-/-) mice. Compared with Klk6+/+ (wild-type) mice, Klk6-/- mice showed milder EAE symptoms, including delayed onset and milder paralysis. Loss of Klk6 suppressed matrix metalloprotease-9 expression and diminished the infiltration of peripheral inflammatory cells into the CNS by decreasing blood-brain barrier (BBB) permeability and reducing expression levels of inflammatory cytokines, chemokines and their receptors. Scanning electron microscopic analysis revealed demyelination characterized by myelin detachment from the axons in the early phase of EAE progression (days 3-7) in Klk6+/+ mice but not in Klk6-/- mice. Interestingly, anti-MOG (myelin oligodendrocyte glycoprotein) autoantibody was also detected in the cerebrospinal fluid (CSF) and spinal cord on day 3 after MOG immunization. Furthermore, treatment of primary cultured OLs with anti-MOG autoantibody induced oligodendroglial morphological changes and increases in myelin basic protein and Klk6 expression. We also developed a novel enzyme-linked immunoabsorbent assay method for detecting activated KLK6 in human CSF. In human autopsy brain samples, expression of active KLK6 was detected in OLs using an antibody that specifically recognizes the protein's activated form. Taken together, our findings demonstrate that Klk6 secreted by OLs plays a critical role in the pathogenesis of EAE/MS and that it might serve as a potential therapeutic target for MS.