Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, United States.
Center for Genetic Medicine Research, Children's Research Institute, Children's National Health System, Washington, DC, United States.
Front Immunol. 2021 Aug 24;12:710608. doi: 10.3389/fimmu.2021.710608. eCollection 2021.
Aging adversely affects inflammatory processes in the brain, which has important implications in the progression of neurodegenerative disease. Following traumatic brain injury (TBI), aged animals exhibit worsened neurological function and exacerbated microglial-associated neuroinflammation. Type I Interferons (IFN-I) contribute to the development of TBI neuropathology. Further, the Cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING) pathway, a key inducer of IFN-I responses, has been implicated in neuroinflammatory activity in several age-related neurodegenerative diseases. Here, we set out to investigate the effects of TBI on cGAS/STING activation, IFN-I signaling and neuroinflammation in young and aged C57Bl/6 male mice. Using a controlled cortical impact model, we evaluated transcriptomic changes in the injured cortex at 24 hours post-injury, and confirmed activation of key neuroinflammatory pathways in biochemical studies. TBI induced changes were highly enriched for transcripts that were involved in inflammatory responses to stress and host defense. Deeper analysis revealed that TBI increased expression of IFN-I related genes (e.g. Ifnb1, Irf7, Ifi204, Isg15) and IFN-I signaling in the injured cortex of aged compared to young mice. There was also a significant age-related increase in the activation of the DNA-recognition pathway, cGAS, which is a key mechanism to propagate IFN-I responses. Finally, enhanced IFN-I signaling in the aged TBI brain was confirmed by increased phosphorylation of STAT1, an important IFN-I effector molecule. This age-related activation of cGAS and IFN-I signaling may prove to be a mechanistic link between microglial-associated neuroinflammation and neurodegeneration in the aged TBI brain.
衰老会对大脑中的炎症过程产生不利影响，这对神经退行性疾病的进展具有重要意义。在创伤性脑损伤 (TBI) 后，老年动物表现出更严重的神经功能障碍和加剧的小胶质细胞相关神经炎症。I 型干扰素 (IFN-I) 有助于 TBI 神经病理学的发展。此外，环鸟苷酸-腺苷酸合成酶 (cGAS) 和干扰素基因刺激物 (STING) 途径是 IFN-I 反应的关键诱导剂，已被牵连到几种与年龄相关的神经退行性疾病中的神经炎症活性。在这里，我们着手研究 TBI 对年轻和老年 C57Bl/6 雄性小鼠大脑中 cGAS/STING 激活、IFN-I 信号转导和神经炎症的影响。使用控制皮质撞击模型，我们在损伤后 24 小时评估了损伤皮质中的转录组变化，并在生化研究中证实了关键神经炎症途径的激活。TBI 诱导的变化高度富集了涉及应激和宿主防御的炎症反应的转录物。更深入的分析表明，TBI 增加了 IFN-I 相关基因（例如 Ifnb1、Irf7、Ifi204、Isg15）的表达和 IFN-I 在老年小鼠受伤皮质中的信号转导。年龄相关的 cGAS 激活也显著增加，cGAS 是传播 IFN-I 反应的关键机制。最后，通过增加重要 IFN-I 效应分子 STAT1 的磷酸化，证实了老年 TBI 大脑中 IFN-I 信号的增强。这种与年龄相关的 cGAS 和 IFN-I 信号转导的激活可能证明是老年 TBI 大脑中小胶质细胞相关神经炎症和神经变性之间的机制联系。
