The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention
The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention
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DOI：
10.1186/1742-2094-10-124
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发表时间：
2013-10-11
影响因子：
9.3
通讯作者：
Brenner, Talma
中科院分区：
文献类型：
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作者：
Gur-Wahnon, Devorah;Mizrachi, Tehila;Brenner, Talma
背景：细胞外蛋白酶如纤溶酶原激活剂（PAs）和基质金属蛋白酶调节细胞-细胞和细胞-基质相互作用。PA/纤溶酶系统的成分已被证明在炎症区域增加，并被认为在炎症性神经系统疾病如癫痫、中风、脑外伤、阿尔茨海默病和多发性硬化症（MS）中发挥作用。在本研究中，我们评估了PA系统在MS动物模型，实验性自身免疫性脑脊髓炎（EAE）中的参与。方法：用髓鞘少突胶质细胞糖蛋白（MOG）诱导尿激酶PA（uPA(-/-)）或尿激酶PA受体（uPAR(-/-)）缺失小鼠EAE。评估小鼠的EAE临床体征和组织病理学参数，并与野生型EAE小鼠进行比较。对敲除（KO）和WT小鼠的淋巴细胞进行体外再刺激、细胞因子分泌和抗原呈递分析。最后，用PA抑制剂蛋白（PAI-1）衍生的18个氨基酸肽PAI-1dp治疗WT EAE小鼠。结果：uPA（-/-）和uPAR（-/-）小鼠EAE加重，并伴有更严重的组织病理特征和小胶质细胞激活。相比之下，KO动物对致脑性抗原MOG的特异性t细胞反应性明显降低，这表明这些小鼠的增殖和促炎细胞因子分泌明显减少。所有KO动物的抗原呈递也减少了，这引起了免疫学上的矛盾。当小鼠接受PA系统衍生的肽PAI-1治疗时，EAE明显改善。临床改善与t细胞反应性降低有关，进一步强调了PA系统在神经炎症期间免疫调节中的重要性。结论：总的来说，我们的研究结果表明uPA和uPAR在EAE的发病机制中起作用，因为在没有uPA和uPAR的情况下，疾病会加剧。此外，通过PAI-1治疗EAE的成功改善表明，PA系统可以被认为是神经免疫性疾病治疗干预的潜在部位。
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.