Identifying the Role of Complement in Triggering Neuroinflammation after Traumatic Brain Injury
Identifying the Role of Complement in Triggering Neuroinflammation after Traumatic Brain Injury
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DOI：
10.1523/jneurosci.2197-17.2018
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发表时间：
2018-03-07
影响因子：
5.3
通讯作者：
Tomlinson, Stephen
中科院分区：
文献类型：
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作者：
Alawieh, Ali;Langley, E. Farris;Tomlinson, Stephen
补体系统参与促进创伤性脑损伤（TBI）后的急性继发性损伤，但其在慢性创伤后神经病理学中的作用仍不清楚。使用各种损伤部位靶向补体抑制剂，阻断不同的补体途径和激活产物，我们研究了补体是如何参与TBI后的神经变性和慢性神经炎症在临床相关的补体抑制设置。目前的范例是补体主要通过终末膜攻击复合物（MAC）传播TBI后神经病理学，但重点是急性结果。在成年雄性小鼠中进行受控皮质撞击后，我们证明，尽管MAC（用CR2-CD 59）的抑制可减少急性缺陷，但需要抑制C3激活以防止慢性炎症和持续的神经元丢失。C3的激活引发了小胶质细胞和星形胶质细胞激活的持续退行性机制，降低了树突和突触密度，并抑制了TBI后几周的神经母细胞迁移。此外，抑制所有补体途径（用CR2-Crry）或仅抑制替代补体途径（用CR2-fH），在慢性组织学、认知和功能恢复方面提供了相似且显著的改善，表明替代途径在传播慢性TBI后病理中的关键作用。虽然我们证实了MAC在TBI后急性神经元丢失中的作用，但本研究表明，主要通过旁路途径产生的补体激活的上游产物传播慢性神经炎症，从而挑战了MAC代表治疗TBI的治疗靶点的当前概念。CR2 fH的人源化版本已在临床试验中显示出安全且无免疫原性。
The complement system is implicated in promoting acute secondary injury after traumatic brain injury (TBI), but its role in chronic post-traumatic neuropathology remains unclear. Using various injury-site targeted complement inhibitors that block different complement pathways and activation products, we investigated how complement is involved in neurodegeneration and chronic neuroinflammation after TBI in a clinically relevant setting of complement inhibition. The current paradigm is that complement propagates post-TBI neuropathology predominantly through the terminal membrane attack complex (MAC), but the focus has been on acute outcomes. Following controlled cortical impact in adult male mice, we demonstrate that although inhibition of the MAC (with CR2-CD59) reduces acute deficits, inhibition of C3 activation is required to prevent chronic inflammation and ongoing neuronal loss. Activation of C3 triggered a sustained degenerative mechanism of microglial and astrocyte activation, reduced dendritic and synaptic density, and inhibited neuroblast migration several weeks after TBI. Moreover, inhibiting all complement pathways (with CR2-Crry), or only the alternative complement pathway (with CR2-fH), provided similar and significant improvements in chronic histological, cognitive, and functional recovery, indicating a key role for the alternative pathway in propagating chronic post-TBI pathology. Although we confirm a role for the MAC in acute neuronal loss after TBI, this study shows that upstream products of complement activation generated predominantly via the alternative pathway propagate chronic neuroinflammation, thus challenging the current concept that the MAC represents a therapeutic target for treating TBI. A humanized version of CR2fH has been shown to be safe and non-immunogenic in clinical trials.