Medical Scientist Training Program and Departments of.
Microbiology and Immunology.
J Neurosci. 2018 Mar 7;38(10):2519-2532. doi: 10.1523/JNEUROSCI.2197-17.2018. Epub 2018 Feb 6.
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. Complement, and specifically the terminal membrane attack complex, has been implicated in secondary injury and neuronal loss after TBI. However, we demonstrate here that upstream complement activation products, generated predominantly via the alternative pathway, are responsible for propagating chronic inflammation and injury following CCI. Chronic inflammatory microgliosis is triggered by sustained complement activation after CCI, and is associated with chronic loss of neurons, dendrites and synapses, a process that continues to occur even 30 d after initial impact. Acute and injury-site targeted inhibition of the alternative pathway significantly improves chronic outcomes, and together these findings modify the conceptual paradigm for targeting the complement system to treat TBI.
补体系统被认为参与了创伤性脑损伤（TBI）后的急性继发性损伤，但它在慢性创伤后神经病理学中的作用尚不清楚。本研究使用了各种损伤部位靶向的补体抑制剂，这些抑制剂可阻断不同的补体途径和激活产物，旨在研究补体在临床上相关的补体抑制环境中是如何参与 TBI 后的神经退行性变和慢性神经炎症的。目前的范式是补体主要通过末端膜攻击复合物（MAC）来传播 TBI 后的神经病理学，但研究重点一直是急性结果。在成年雄性小鼠的皮质控制冲击后，我们发现尽管抑制 MAC（用 CR2-CD59）可减轻急性缺陷，但抑制 C3 激活是预防慢性炎症和持续神经元丢失所必需的。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，减少了树突和突触密度，并在 TBI 后数周抑制神经母细胞迁移。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均提供了类似且显著的改善，表明替代途径在传播慢性 TBI 病理方面起着关键作用。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，补体激活的上游产物主要通过替代途径产生，可传播慢性神经炎症，从而挑战了 MAC 代表治疗 TBI 的治疗靶点的当前概念。在临床试验中，已经显示人源化的 CR2fH 是安全且非免疫原性的。补体，特别是末端膜攻击复合物，已被认为与 TBI 后的继发性损伤和神经元丢失有关。然而，我们在此证明，主要通过替代途径产生的补体激活上游产物是导致 CCI 后慢性炎症和损伤的原因。CCI 后持续的补体激活引发慢性炎症性小胶质细胞激活，并与神经元、树突和突触的慢性丢失相关，即使在最初撞击后 30 d，该过程仍在继续。急性和损伤部位靶向的替代途径抑制可显著改善慢性结果，这些发现共同改变了针对补体系统治疗 TBI 的概念范式。
