Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425.
Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia 30322.
J Neurosci. 2021 Feb 24;41(8):1830-1843. doi: 10.1523/JNEUROSCI.1734-20.2020. Epub 2021 Jan 14.
Cognitive deficits following traumatic brain injury (TBI) remain a major cause of disability and early-onset dementia, and there is increasing evidence that chronic neuroinflammation occurring after TBI plays an important role in this process. However, little is known about the molecular mechanisms responsible for triggering and maintaining chronic inflammation after TBI. Here, we identify complement, and specifically complement-mediated microglial phagocytosis of synapses, as a pathophysiological link between acute insult and a chronic neurodegenerative response that is associated with cognitive decline. Three months after an initial insult, there is ongoing complement activation in the injured brain of male C57BL/6 mice, which drives a robust chronic neuroinflammatory response extending to both hemispheres. This chronic neuroinflammatory response promotes synaptic degeneration and predicts progressive cognitive decline. Synaptic degeneration was driven by microglial phagocytosis of complement-opsonized synapses in both the ipsilateral and contralateral brain, and complement inhibition interrupted the degenerative neuroinflammatory response and reversed cognitive decline, even when therapy was delayed until 2 months after TBI. These findings provide new insight into our understanding of TBI pathology and its management; and whereas previous therapeutic investigations have focused almost exclusively on acute treatments, we show that all phases of TBI, including at chronic time points after TBI, may be amenable to therapeutic interventions, and specifically to complement inhibition. There is increasing evidence of a chronic neuroinflammatory response after traumatic brain injury (TBI), but little is known about the molecular mechanisms responsible for triggering and maintaining chronic inflammation. We identify complement, and specifically complement-mediated microglial phagocytosis of synapses, as a pathophysiological link between acute insult and a chronic neurodegenerative response, and further that this response is associated with cognitive decline. Complement inhibition interrupted this response and reversed cognitive decline, even when therapy was delayed until 2 months after injury. The data further support the concept that TBI should be considered a chronic rather than an acute disease condition, and have implications for the management of TBI in the chronic phase of injury, specifically with regard to the therapeutic application of complement inhibition.
创伤性脑损伤（TBI）后的认知缺陷仍然是残疾和早发性痴呆的主要原因，越来越多的证据表明，TBI 后发生的慢性神经炎症在这一过程中起着重要作用。然而，对于触发和维持 TBI 后慢性炎症的分子机制知之甚少。在这里，我们确定补体，特别是补体介导的突触小胶质细胞吞噬作用，是急性损伤与与认知能力下降相关的慢性神经退行性反应之间的病理生理学联系。在初始损伤后 3 个月，雄性 C57BL/6 小鼠受伤大脑中持续存在补体激活，导致强烈的慢性神经炎症反应延伸至两个半球。这种慢性神经炎症反应促进突触退化，并预测进行性认知下降。突触退化是由补体调理的突触在同侧和对侧大脑中的小胶质细胞吞噬作用驱动的，补体抑制中断了退行性神经炎症反应并逆转了认知下降，即使在 TBI 后 2 个月才开始治疗也是如此。这些发现为我们理解 TBI 病理学及其管理提供了新的见解；虽然以前的治疗研究几乎完全集中在急性治疗上，但我们表明，TBI 的所有阶段，包括 TBI 后慢性时间点，都可能适合治疗干预，特别是补体抑制。创伤性脑损伤（TBI）后有越来越多的证据表明存在慢性神经炎症反应，但对于触发和维持慢性炎症的分子机制知之甚少。我们确定补体，特别是补体介导的突触小胶质细胞吞噬作用，是急性损伤与慢性神经退行性反应之间的病理生理学联系，进一步表明这种反应与认知能力下降有关。补体抑制中断了这种反应并逆转了认知下降，即使在损伤后 2 个月才开始治疗也是如此。这些数据进一步支持了 TBI 应被视为慢性而非急性疾病状态的概念，并对 TBI 慢性损伤阶段的管理具有重要意义，特别是在补体抑制的治疗应用方面。
