Complement regulator loss on apoptotic neuronal cells causes increased complement activation and promotes both phagocytosis and cell lysis
Complement regulator loss on apoptotic neuronal cells causes increased complement activation and promotes both phagocytosis and cell lysis
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DOI：
10.1016/j.molimm.2005.11.015
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发表时间：
2006-05-01
影响因子：
3.6
通讯作者：
Morgan, B. Paul
中科院分区：
文献类型：
--
作者：
Cole, Duncan S.;Hughes, Timothy R.;Morgan, B. Paul
在神经炎性疾病中，补体（C）活化和神经元凋亡发生在活动性病理区域。C具有清除凋亡碎片的作用，但也已知通过插入膜攻击复合物（MAC）引起坏死性细胞死亡。因此，不清楚在这种情况下，C是保护性的还是有害的。在这里，我们研究C调节器的表达和易感性C激活，裂解和吞噬在人类神经元细胞凋亡，以模拟在体内的情况。我们证明，凋亡的神经细胞系失去了C调节CD 46和CD 59。调节子丢失仅发生在凋亡标记物阳性的细胞上，并且是半胱天冬酶依赖性的。CD 46和CD 59都从细胞脱落，CD 46在MMP裂解后以可溶性形式脱落，而CD 59在凋亡的水泡上以可溶性形式脱落。凋亡细胞激活C和调理更容易比对照细胞，因此，他们更容易被吞噬的巨噬细胞比非凋亡细胞。对C介导的裂解的敏感性是复杂的，因为早期细胞更敏感，而晚期凋亡细胞对杀伤更耐受。MMP抑制保护对早期凋亡细胞中所见的裂解增加，但对非凋亡细胞对C-介导的裂解的敏感性没有影响。我们的研究表明，C激活凋亡的神经元细胞之间的微妙平衡，通过吞噬作用，提高他们的安全处置，并触发C介导的裂解坏死。这些数据表明，通过限制CD 46的损失，治疗性MMP抑制可以限制神经系统疾病中的神经元损伤。(c)2005爱思唯尔有限公司保留所有权利。
In neuroinflammatory disease complement (C) activation and neuronal apoptosis occur in areas of active pathology. C has a role in clearing apoptotic debris, but is also known to cause necrotic cell death by insertion of the membrane attack complex (MAC). It is therefore unclear whether C is protective or injurious in this context. Here we examine C regulator expression and susceptibility to C activation, lysis and phagocytosis in human neuronal cells undergoing apoptosis in order to model the in vivo situation. We demonstrate that apoptotic neuronal lines lose the C regulators CD46 and CD59. Regulator loss occurred only on cells positive for apoptotic markers, and was caspase dependent. Both CD46 and CD59 were shed from cells, CD46 as a Soluble form following MMP cleavage, and CD59 on apoptotic blebs and as a soluble form. Apoptotic cells activated C and were opsonised more readily than control cells; as a consequence they were more readily phagocytosed by macrophages than non-apoptotic cells. Susceptibility to C-mediated lysis was complicated in that early cells were more sensitive while late apoptotic cells were more resistant to killing. MMP inhibition protected against the increased lysis seen in early apoptotic cells, but had no effect on susceptibility of non-apoptotic cells to C-mediated lysis. Our studies suggest that C activation on apoptotic neuronal cells is delicately balanced between enhancing their safe disposal through phagocytosis, and triggering necrosis by C-mediated lysis. The data suggest that therapeutic MMP inhibition, by restricting loss of CD46, may limit neuronal damage in neurological disease. (c) 2005 Elsevier Ltd. All rights reserved.