Izzy Saef, Liu Qiong, Fang Zhou, Lule Sevda, Wu Limin, Chung Joon Yong, Sarro-Schwartz Aliyah, Brown-Whalen Alexander, Perner Caroline, Hickman Suzanne E, Kaplan David L, Patsopoulos Nikolaos A, El Khoury Joseph, Whalen Michael J
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
Front Cell Neurosci. 2019 Aug 8;13:307. doi: 10.3389/fncel.2019.00307. eCollection 2019.
The neuroinflammatory response to traumatic brain injury (TBI) is critical to both neurotoxicity and neuroprotection, and has been proposed as a potentially modifiable driver of secondary injury in animal and human studies. Attempts to broadly target immune activation have been unsuccessful in improving outcomes, in part because the precise cellular and molecular mechanisms driving injury and outcome at acute, subacute, and chronic time points after TBI remain poorly defined. Microglia play a critical role in neuroinflammation and their persistent activation may contribute to long-term functional deficits. Activated microglia are characterized by morphological transformation and transcriptomic changes associated with specific inflammatory states. We analyzed the temporal course of changes in inflammatory genes of microglia isolated from injured brains at 2, 14, and 60 days after controlled cortical impact (CCI) in mice, a well-established model of focal cerebral contusion. We identified a time dependent, injury-associated change in the microglial gene expression profile toward a reduced ability to sense tissue damage, perform housekeeping, and maintain homeostasis in the early stages following CCI, with recovery and transition to a specialized inflammatory state over time. This later state starts at 14 days post-injury and is characterized by a biphasic pattern of IFNγ, IL-4, and IL-10 gene expression changes, with concurrent proinflammatory and anti-inflammatory gene changes. Our transcriptomic data sets are an important step to understand microglial role in TBI pathogenesis at the molecular level and identify common pathways that affect outcome. More studies to evaluate gene expression at the single cell level and focusing on subacute and chronic timepoint are warranted.
创伤性脑损伤（TBI）引发的神经炎症反应对神经毒性和神经保护均至关重要，在动物和人体研究中，它被认为是继发性损伤的一个潜在可调节驱动因素。广泛针对免疫激活的尝试在改善预后方面并未成功，部分原因是在TBI后的急性、亚急性和慢性时间点，驱动损伤和预后的确切细胞和分子机制仍不清楚。小胶质细胞在神经炎症中起关键作用，其持续激活可能导致长期功能缺陷。活化的小胶质细胞的特征是形态转变和与特定炎症状态相关的转录组变化。我们分析了在小鼠控制皮质撞击（CCI）后第2天、第14天和第60天从受伤大脑中分离出的小胶质细胞炎症基因的时间变化过程，CCI是一种成熟的局灶性脑挫伤模型。我们发现，在CCI后的早期阶段，小胶质细胞基因表达谱存在时间依赖性、与损伤相关的变化，表现为感知组织损伤、进行日常维护和维持内环境稳定的能力下降，随着时间推移会恢复并转变为一种特殊的炎症状态。这种后期状态在受伤后14天开始，其特征是IFNγ、IL-4和IL-10基因表达呈双相变化模式，同时存在促炎和抗炎基因变化。我们的转录组数据集是在分子水平上理解小胶质细胞在TBI发病机制中的作用并确定影响预后的共同途径的重要一步。有必要开展更多研究来评估单细胞水平的基因表达，并关注亚急性和慢性时间点。
