Activation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

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慢性补体失调驱动创伤性脑损伤后的神经炎症：转录组学研究

补体系统的激活会在创伤性脑损伤 (TBI) 后早期和长期地传播神经炎症和脑损伤。补体系统很复杂，包含 50 多种成分，其中许多成分在正常和受伤的大脑中仍有待表征。此外，补体治疗研究集中在数量有限的组织病理学结果上，这些结果虽然信息丰富，但并未全面评估补体抑制对神经保护和炎症的影响。使用高通量基因表达技术 (NanoString)，我们同时分析了 TBI 后不同时间点与其他神经炎症通路基因的补体基因表达谱。我们还评估了补体抑制对神经病理学过程的影响。在受控皮质撞击损伤后，雄性 C57BL/6 小鼠在损伤后第 3、7 和 28 天进行神经炎症基因分析。我们还描述了 59 种补体基因在相似时间点以及受伤后 1 年和 2 年的表达。总体而言，从损伤后第 3 天到第 28 天，TBI 上调了星形胶质细胞增生、免疫细胞激活和细胞应激标志物的表达，并下调了神经元和突触标志物的表达。此外，TBI 上调了大多数补体激活和效应途径的基因表达，早期强调经典途径基因，并在损伤后 2 年继续上调 C2、C3 和 C4 表达。使用靶向补体抑制剂 CR2-Crry 进行治疗，在所有时间点显着改善了 TBI 诱导的转录组变化。然而，一些免疫和突触基因在 CR2-Crry 治疗中仍然失调，这表明辅助抗炎和嗜神经治疗可能会带来额外的神经保护作用。除了表征正常和衰老大脑中的补体基因表达外，我们的结果还证明了 TBI 后补体系统的广泛和慢性失调，并加强了补体系统是 TBI 治疗的有吸引力的目标的观点。