Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation
Dual inhibition of proteasomal and lysosomal proteolysis ameliorates autoimmune central nervous system inflammation
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DOI：
10.1002/eji.200838413
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发表时间：
2008-09-01
影响因子：
5.4
通讯作者：
Weissert, Robert
中科院分区：
文献类型：
--
作者：
Fissolo, Nicolas;Kraus, Marianne;Weissert, Robert
多发性硬化症(MS)是一种导致长期残疾的中枢神经系统(CNS)疾病。在多发性硬化症(实验性自身免疫性脑脊髓炎)的动物模型过程中，我们发现中枢神经系统蛋白酶体亚基β1I、β2、β2I和β5的活性增强。我们证明，在预防性和治疗性治疗中，Bortezomib对蛋白酶体的药理抑制可以改善小鼠和大鼠的实验性自身免疫性脑脊髓炎，减少分泌促炎细胞因子的T细胞数量。蛋白酶体抑制的抗炎作用伴随着中枢和淋巴器官中核因子-kappaB活性的降低。参与主要组织相容性复合体II抗原呈递的蛋白酶体和溶酶体蛋白的联合抑制进一步提高了治疗效果。我们建议单独抑制蛋白酶体或联合抑制溶酶体蛋白水解酶作为对抗炎症诱导的中枢神经系统变性的一种新的治疗策略。我们展示了蛋白酶体和溶酶体蛋白对自身免疫发展的影响。
Multiple sclerosis (MS) is a detrimental disease of the central nervous system (CNS) leading to long-term disability. in the course of animal models of multiple sclerosis (experimental autoimmune encephalomyelitis), we find enhanced activity of proteasome subunits beta 1i, beta 2, beta 2i and beta 5 in the CNS. We demonstrate that pharmacological inhibition of the proteasome by bortezomib ameliorates experimental autoimmune encephalomyelitis in mice and rats in prophylactic and therapeutic treatment with reduced numbers of T-cells secreting proinflammatory cytokines. The anti-inflammatory effect of proteasome inhibition was accompanied by reduced NF-kappa B activity in the CNS and lymphoid organs. The combined inhibition of proteasomes and lysosomal proteases involved in major histocompatibility complex II antigen presentation further improved therapeutic efficacy. We suggest proteasome inhibition alone or in combination with inhibition of lysosomal proteases as a novel therapeutic strategy against inflammation-induced neurodegeneration in the CNS. We demonstrate the impact of the proteasome and lysosomal proteases on development of autoimmunity.