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首页> 外文期刊>Journal of neuroinflammation >The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention
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The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention

机译：纤溶酶原激活剂系统：参与中枢神经系统炎症和潜在的治疗干预部位

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Background Extracellular proteases such as plasminogen activators (PAs) and matrix metalloproteinases modulate cell-cell and cell-matrix interactions. Components of the PA/plasmin system have been shown to be increased in areas of inflammation, and have been suggested to play a role in inflammatory neurologic disorders such as epilepsy, stroke, brain trauma, Alzheimer's' disease and multiple sclerosis (MS). In the present study, we evaluated the involvement of the PA system in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). Methods EAE was induced by myelin oligodendrocyte glycoprotein (MOG) in mice deficient for the urokinase PA (uPA?/?), or the urokinase PA receptor (uPAR?/?). Mice were evaluated for EAE clinical signs and histopathologic parameters, and compared with wild-type (WT) EAE mice. Lymphocytes from the knockout (KO) and WT mice were analyzed for ex vivo restimulation, cytokine secretion, and antigen presentation. Finally, WT EAE mice were treated with PAI-1dp, an 18 amino acid peptide derived from the PA inhibitor protein (PAI-1). Results EAE was aggravated in uPA?/? and uPAR?/? mice, and this was accompanied by more severe histopathologic features and microglial activation. By contrast, specific T- cell reactivity towards the encephalitogenic antigen MOG was markedly reduced in the KO animals, as shown by a marked reduction in proliferation and pro-inflammatory cytokine secretion in these mice. Antigen presentation was also reduced in all the KO animals, raising an immunologic paradox. When the mice were treated with PAI-1, a peptide derived from the PA system, a marked and significant improvement in EAE was seen. The clinical improvement was linked to reduced T-cell reactivity, further emphasizing the importance of the PA system in immunomodulation during neuroinflammation. Conclusions Cumulatively, our results suggest a role for uPA and uPAR in EAE pathogenesis, as exacerbation of disease was seen in their absence. Furthermore, the successful amelioration of EAE by PAI-1 treatment suggests that the PA system can be considered a potential site for therapeutic intervention in the treatment of neuroimmune diseases.
机译：背景技术诸如纤溶酶原激活物（PAs）和基质金属蛋白酶的细胞外蛋白酶调节细胞-细胞和细胞-基质的相互作用。已显示，PA /纤溶酶系统的成分在炎症区域增加，并被建议在炎症性神经疾病中起作用，例如癫痫，中风，脑外伤，阿尔茨海默氏病和多发性硬化症（MS）。在本研究中，我们评估了PA系统在MS动物模型中的作用，即实验性自身免疫性脑脊髓炎（EAE）。方法用髓磷脂少突胶质细胞糖蛋白（MOG）在缺乏尿激酶PA（uPAα/β）或尿激酶PA受体（uPARβ/β）的小鼠中诱发EAE。评价小鼠的EAE临床体征和组织病理学参数，并与野生型（WT）EAE小鼠进行比较。分析了来自敲除小鼠（KO）和野生型小鼠的淋巴细胞的离体再刺激，细胞因子分泌和抗原呈递。最后，用PAI-1dp治疗WT EAE小鼠，PAI-1dp是一种来自PA抑制剂蛋白（PAI-1）的18个氨基酸的肽。结果uPA？/？中EAE加剧。和uPAR？/？并伴有更严重的组织病理学特征和小胶质细胞活化。相反，在KO动物中，针对脑致病抗原MOG的特异性T细胞反应性显着降低，如这些小鼠中增殖和促炎性细胞因子分泌的显着降低所表明的。在所有KO动物中，抗原呈递也减少了，从而引发了免疫学悖论。当用PAI-1（一种来自PA系统的肽）对小鼠进行治疗时，可以看到EAE的显着显着改善。临床改善与降低的T细胞反应性有关，进一步强调了PA系统在神经炎症过程中免疫调节中的重要性。结论累积地，我们的结果表明uPA和uPAR在EAE发病机理中的作用，因为在它们不存在的情况下会加剧疾病。此外，通过PAI-1治疗成功改善了EAE，表明PA系统可被视为治疗神经免疫疾病的潜在治疗手段。

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