Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy.
Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy.
复制标题
DOI：
10.1002/glia.22534
复制
发表时间：
2013-09
期刊：
影响因子：
6.2
通讯作者：
Scarisbrick, Isobel A.
中科院分区：
文献类型：
--
作者：
Burda, Joshua E.;Radulovic, Maja;Yoon, Hyesook;Scarisbrick, Isobel A.
Kallikrein 6 （Klk6）是一种分泌丝氨酸蛋白酶，在中枢神经系统白质中由少突胶质细胞优先表达。Klk6水平升高发生在主动脱髓鞘多发性硬化症（MS）病变、脊髓损伤（SCI）、中风和胶质母细胞瘤病例中。最近有证据表明Klk6是cns内源性蛋白酶激活受体（PARs）的激活剂，我们假设Klk6激活PARs的一个子集来调节少突胶质细胞的生理和潜在的病理生理。本研究使用野生型或par1缺失小鼠和小鼠少突胶质细胞系Oli-neu培养的原代少突胶质细胞来证明，Klk6介导少突胶质细胞过程的缺失，并以par1依赖的方式阻碍少突胶质细胞祖细胞（OPCs）的形态分化。典型的PAR1激动剂、凝血酶以及PAR1激活肽（PAR1- aps）也可引起类似的胶质病变。在体外实验中，Klk6也加重了atp介导的少突胶质病变，表明其在增强兴奋毒性方面具有潜在作用。此外，Klk6通过par1介导的Erk1/2信号通路抑制培养少突胶质细胞中蛋白脂质蛋白（PLP） RNA的表达。将PAR1激动剂（包括Klk6或PAR1- aps）显微注射到PAR+/+而不是PAR - / -小鼠的背柱白质中，可促进空泡性脊髓病和髓鞘碱性蛋白（MBP）和CC-1+少突胶质细胞的免疫反应性丧失。这些结果证明了Klk6-PAR1信号在少突胶质病理生理中的功能作用，并表明PAR1或PAR1激动剂可能是中枢神经系统白质损伤或疾病病例中缓解脱髓鞘和促进髓鞘再生的新靶点。
Kallikrein 6 (Klk6) is a secreted serine protease preferentially expressed by oligodendroglia in CNS white matter. Elevated levels of Klk6 occur in actively demyelinating multiple sclerosis (MS) lesions and in cases of spinal cord injury (SCI), stroke and glioblastoma. Taken with recent evidence establishing Klk6 as a CNS-endogenous activator of protease-activated receptors (PARs), we hypothesized that Klk6 activates a subset of PARs to regulate oligodendrocyte physiology and potentially pathophysiology. Here, primary oligodendrocyte cultures derived from wild type or PAR1-deficient mice and the murine oligodendrocyte cell line, Oli-neu, were used to demonstrate that Klk6 mediates loss of oligodendrocyte processes and impedes morphological differentiation of oligodendrocyte progenitor cells (OPCs) in a PAR1-dependent fashion. Comparable gliopathy was also elicited by the canonical PAR1 agonist, thrombin, as well as PAR1-activating peptides (PAR1-APs). Klk6 also exacerbated ATP-mediated oligodendrogliopathy in vitro, pointing to a potential role in augmenting excitotoxicity. In addition, Klk6 suppressed the expression of proteolipid protein (PLP) RNA in cultured oligodendrocytes by a mechanism involving PAR1-mediated Erk1/2 signaling. Microinjection of PAR1 agonists, including Klk6 or PAR1-APs, into the dorsal column white matter of PAR+/+ but not PAR−/− mice promoted vacuolating myelopathy and a loss of immunoreactivity for myelin basic protein (MBP) and CC-1+ oligodendrocytes. These results demonstrate a functional role for Klk6-PAR1 signaling in oligodendroglial pathophysiology and suggest that PAR1 or PAR1-agonists may represent new targets to moderate demyelination and to promote myelin regeneration in cases of CNS white matter injury or disease.
登录
查看更多内容
DOI：
10.1083/jcb.85.3.890
发表时间：
1980-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
McCarthy KD;de Vellis J
通讯作者：
de Vellis J
影响因子：
4.8
作者：
Angelo, PF;Lima, AR;Juliano, MA
通讯作者：
Juliano, MA
影响因子：
158.5
作者：
Chang, A;Tourtellotte, WW;Trapp, BD
通讯作者：
Trapp, BD
影响因子：
2.9
作者：
Blaber, SI;Scarisbrick, IA;Blaber, M
通讯作者：
Blaber, M
影响因子：
4.7
作者：
Juliet, Packiasamy A. R.;Frost, Emma E.;Del Bigio, Marc R.
通讯作者：
Del Bigio, Marc R.