Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, BSB 204, MSC 504, Charleston, SC, 29425, USA.
Ralph Johnson VA Medical Center, Charleston, SC, 29401, USA.
Acta Neuropathol Commun. 2021 Jul 19;9(1):126. doi: 10.1186/s40478-021-01226-2.
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.
补体系统的激活会在创伤性脑损伤（TBI）后早期和慢性引发神经炎症和脑损伤。补体系统非常复杂，包含 50 多种成分，其中许多在正常和受损的大脑中仍有待研究。此外，补体治疗研究主要集中在少数组织病理学结果上，这些结果虽然具有信息性，但不能全面评估补体抑制对神经保护和炎症的影响。我们使用高通量基因表达技术（NanoString），同时分析了 TBI 后不同时间点补体基因表达谱和其他神经炎症途径基因。我们还评估了补体抑制对神经病理过程的影响。在雄性 C57BL/6 小鼠中进行了皮质撞击伤后，在第 3、7 和 28 天进行了神经炎症基因分析。我们还在类似的时间点以及伤后 1 年和 2 年时，对 59 种补体基因的表达进行了特征描述。总的来说，TBI 上调了星形胶质细胞、免疫细胞激活和细胞应激的标志物的表达，下调了神经元和突触标志物的表达，从伤后第 3 天到第 28 天。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，并且在伤后 2 年时 C2、C3 和 C4 的表达持续上调。使用靶向补体抑制剂 CR2-Crry 治疗显著改善了 TBI 诱导的所有时间点的转录组变化。然而，CR2-Crry 治疗后一些免疫和突触基因仍然失调，这表明辅助抗炎和神经营养治疗可能会提供额外的神经保护。除了对正常和衰老大脑中的补体基因表达进行特征描述外，我们的结果还表明，TBI 后补体系统会发生广泛且慢性的失调，并且加强了补体系统是 TBI 治疗的一个有吸引力的靶点的观点。
Zotero 插件
