The role of TRAIL/TRAIL receptors in central nervous system pathology
The role of TRAIL/TRAIL receptors in central nervous system pathology
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DOI：
10.2741/2281
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发表时间：
2007-05-01
影响因子：
3.1
通讯作者：
Zipp, Frauke
中科院分区：
文献类型：
--
作者：
Aktas, Orhan;Schulze-Topphoff, Ulf;Zipp, Frauke
最初，肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）由于其对恶性细胞的优先毒性作用而引起了人们的极大兴趣。然而，随后的研究表明，包括信号介导和诱饵TRAIL受体家族的TRAIL系统（i）也可以诱导非转化细胞的死亡，（ii）具有有效的免疫调节功能，和（iii）在中枢神经系统（CNS）中表现出独特的表达模式。事实上，TRAIL在人脑中不表达，而在神经元、少突胶质细胞和星形胶质细胞上发现了不同分布的诱导凋亡的TRAIL受体。这些发现排除了TRAIL对大脑所谓的“免疫赦免”的主要贡献，其中局部炎症是有限的，尽管先前已经提出了属于相同TNF/神经生长因子（NGF）家族的CD95（Fas）配体的这种作用。如果在病理情况下CNS发炎，则免疫细胞如巨噬细胞和T细胞在活化后上调TRAIL，并使用这种死亡配体作为武器，不仅针对肿瘤细胞，而且针对发炎CNS内的神经元和少突胶质细胞。同时，也显示了TRAIL对脑外致脑炎性T细胞的活化和增殖的深刻的免疫调节影响。因此，这些研究揭示了TRAIL对CNS病理学的复杂作用，表明靶向操纵TRAIL系统用于治疗炎性神经变性疾病如多发性硬化症的可能价值。
Initially, the tumor necrosis factor (TNF)-related apoptosis-inducing ligand ( TRAIL) aroused major interest due to its preferential toxic effect against malignant cells. However, subsequent studies revealed that the TRAIL system, comprising the family of signal-mediating and decoy TRAIL receptors, (i) can also induce death of non-transformed cells, (ii) has potent immunoregulatory functions, and (iii) exhibits a unique expression pattern in the central nervous system (CNS). Indeed, TRAIL is not expressed within the human brain, while apoptosis-inducing TRAIL receptors are found differently distributed on neurons, oligodendrocytes, and astrocytes. These findings rule out a major contribution of TRAIL to the so-called "immune privilege" of the brain, in which local inflammation is limited, although such a role has previously been suggested for the CD95 (Fas) ligand belonging to the same TNF/nerve growth factor (NGF) family. If, under pathologic circumstances, the CNS is inflamed, immune cells such as macrophages and T cells upregulate TRAIL upon activation and use this death ligand as a weapon, not only against tumor cells but also against neurons and oligodendrocytes within the inflamed CNS. In parallel, a profound immunoregulatory impact of TRAIL on activation and proliferation of encephalitogenic T cells outside the brain has also been shown. Thus, these studies have uncovered a complex action of TRAIL on CNS pathology, indicating the possible value of targeted manipulation of the TRAIL system for the treatment of inflammatory neurodegenerative diseases such as multiple sclerosis.