Zheng Xiaojing, Mi Tiantian, Wang Rong, Zhang Zihan, Li Wenyan, Zhao Junli, Yang Peiyan, Xia Haibin, Mao Qinwen
Laboratory of Gene Therapy, Department of Biochemistry, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China.
Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
Glia. 2022 Jul;70(7):1317-1336. doi: 10.1002/glia.24175. Epub 2022 Apr 1.
Traumatic brain injury (TBI) can be progressive and can lead to the development of a long-term complication termed chronic traumatic encephalopathy. The mechanisms underlying the progressive changes are still unknown; however, studies have suggested that microglia-mediated neuroinflammation in response to TBI may play a fundamental role. This study aimed to determine whether progranulin (PGRN), a major modulator of microglial activity, plays a role in the progressive damage following TBI. PGRN-deficient and wild-type mice were subjected to controlled cortical impact and were observed neuropathologically after 3 days, 7 days, and 5 months. Compared to sham and wild-type mice, the PGRN-deficient mice showed overall stronger microgliosis and astrocytosis. The astrocytosis involved broader areas than the microgliosis and was more prominent in the basal ganglia, hippocampus, and internal capsule in PGRN-deficient mice. Ongoing neuronal death was uniquely observed in the hippocampal CA3 region of PGRN-deficient mice at 5 months after TBI, accompanying the regional chronic microgliosis and astrocytosis involving the CA3 commissural pathway. In addition, there was M1 microglial polarization in the pericontusional area with activated TLR4/MyD88/NF-κB signaling; however, the hippocampus showed only mild M1 polarization 7 days after TBI. Lastly, Morris water maze tests showed PGRN-deficient mice had poorer spatial learning and memory 5 months after TBI than wild-type or sham mice. The data indicated the PGRN deficiency caused TBI progression by promoting persistent microgliosis with microglial polarization and astrocytosis, as well as regional pathology in the hippocampus. The study suggests that PGRN should be evaluated as a potential therapy for TBI.
创伤性脑损伤（TBI）可能会进展，并导致一种称为慢性创伤性脑病的长期并发症的发生。这种进展性变化的潜在机制仍然未知；然而，研究表明，小胶质细胞介导的对TBI的神经炎症反应可能起着根本性作用。本研究旨在确定前颗粒蛋白（PGRN），一种小胶质细胞活性的主要调节因子，是否在TBI后的进展性损伤中发挥作用。对缺乏PGRN的小鼠和野生型小鼠进行控制性皮质撞击，并在3天、7天和5个月后进行神经病理学观察。与假手术组和野生型小鼠相比，缺乏PGRN的小鼠总体上显示出更强的小胶质细胞增生和星形胶质细胞增生。星形胶质细胞增生涉及的区域比小胶质细胞增生更广，并且在缺乏PGRN的小鼠的基底神经节、海马和内囊中更为突出。在TBI后5个月，在缺乏PGRN的小鼠的海马CA3区独特地观察到持续的神经元死亡，伴随着涉及CA3连合通路的局部慢性小胶质细胞增生和星形胶质细胞增生。此外，在挫伤周围区域有M1小胶质细胞极化，伴有TLR4/MyD88/NF-κB信号激活；然而，在TBI后7天，海马仅显示轻度的M1极化。最后，莫里斯水迷宫试验表明，在TBI后5个月，缺乏PGRN的小鼠比野生型或假手术组小鼠的空间学习和记忆能力更差。数据表明，PGRN缺乏通过促进持续的小胶质细胞增生、小胶质细胞极化和星形胶质细胞增生以及海马的局部病理改变导致TBI进展。该研究表明，PGRN应作为TBI的一种潜在治疗方法进行评估。
