Department of Anesthesiology and Shock, Trauma, and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21201,
Department of Anesthesiology and Shock, Trauma, and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21201.
J Neurosci. 2020 Mar 11;40(11):2357-2370. doi: 10.1523/JNEUROSCI.2516-19.2020. Epub 2020 Feb 6.
DNA damage and type I interferons (IFNs) contribute to inflammatory responses after traumatic brain injury (TBI). TBI-induced activation of microglia and peripherally-derived inflammatory macrophages may lead to tissue damage and neurological deficits. Here, we investigated the role of IFN-β in secondary injury after TBI using a controlled cortical impact model in adult male IFN-β-deficient (IFN-β) mice and assessed post-traumatic neuroinflammatory responses, neuropathology, and long-term functional recovery. TBI increased expression of DNA sensors cyclic GMP-AMP synthase and stimulator of interferon genes in wild-type (WT) mice. IFN-β and other IFN-related and neuroinflammatory genes were also upregulated early and persistently after TBI. TBI increased expression of proinflammatory mediators in the cortex and hippocampus of WT mice, whereas levels were mitigated in IFN-β mice. Moreover, long-term microglia activation, motor, and cognitive function impairments were decreased in IFN-β TBI mice compared with their injured WT counterparts; improved neurological recovery was associated with reduced lesion volume and hippocampal neurodegeneration in IFN-β mice. Continuous central administration of a neutralizing antibody to the IFN-α/β receptor (IFNAR) for 3 d, beginning 30 min post-injury, reversed early cognitive impairments in TBI mice and led to transient improvements in motor function. However, anti-IFNAR treatment did not improve long-term functional recovery or decrease TBI neuropathology at 28 d post-injury. In summary, TBI induces a robust neuroinflammatory response that is associated with increased expression of IFN-β and other IFN-related genes. Inhibition of IFN-β reduces post-traumatic neuroinflammation and neurodegeneration, resulting in improved neurological recovery. Thus, IFN-β may be a potential therapeutic target for TBI. TBI frequently causes long-term neurological and psychiatric changes in head injury patients. TBI-induced secondary injury processes including persistent neuroinflammation evolve over time and can contribute to chronic neurological impairments. The present study demonstrates that TBI is followed by robust activation of type I IFN pathways, which have been implicated in microglial-associated neuroinflammation and chronic neurodegeneration. We examined the effects of genetic or pharmacological inhibition of IFN-β, a key component of type I IFN mechanisms to address its role in TBI pathophysiology. Inhibition of IFN-β signaling resulted in reduced neuroinflammation, attenuated neurobehavioral deficits, and limited tissue loss long after TBI. These preclinical findings suggest that IFN-β may be a potential therapeutic target for TBI.
DNA 损伤和 I 型干扰素（IFNs）有助于创伤性脑损伤（TBI）后的炎症反应。TBI 诱导的小胶质细胞和外周衍生的炎症巨噬细胞的激活可能导致组织损伤和神经功能缺损。在这里，我们使用成年雄性 IFN-β 缺陷（IFN-β）小鼠的皮质控制冲击模型研究了 IFN-β 在 TBI 后的继发性损伤中的作用，并评估了创伤后神经炎症反应、神经病理学和长期功能恢复。TBI 增加了野生型（WT）小鼠中环鸟苷酸-AMP 合酶和干扰素基因刺激物（STING）等 DNA 传感器的表达。IFN-β 和其他 IFN 相关和神经炎症基因也在 TBI 后早期和持续上调。TBI 增加了 WT 小鼠皮质和海马中促炎介质的表达，而 IFN-β 小鼠中的水平则减轻。此外，与受伤的 WT 对照相比，IFN-β TBI 小鼠的长期小胶质细胞激活、运动和认知功能障碍减少；IFN-β 小鼠的神经功能恢复较好与病变体积减少和海马神经退行性变有关。连续 3 天（伤后 30 分钟开始）给予 IFN-α/β 受体（IFNAR）的中和抗体可逆转 TBI 小鼠的早期认知障碍，并导致运动功能的短暂改善。然而，抗 IFNAR 治疗并不能改善 28 天后的长期功能恢复或减少 TBI 神经病理学。总之，TBI 诱导强烈的神经炎症反应，与 IFN-β 和其他 IFN 相关基因的表达增加有关。IFN-β 抑制减少创伤后神经炎症和神经退行性变，导致神经功能恢复改善。因此，IFN-β 可能是 TBI 的潜在治疗靶点。TBI 经常导致头部受伤患者出现长期的神经和精神变化。TBI 诱导的继发性损伤过程包括持续的神经炎症，随着时间的推移而演变，并可能导致慢性神经损伤。本研究表明，TBI 后会强烈激活 I 型 IFN 途径，该途径与小胶质细胞相关的神经炎症和慢性神经退行性变有关。我们研究了遗传或药理学抑制 IFN-β（I 型 IFN 机制的关键组成部分）对 TBI 发病机制的作用。IFN-β 信号通路的抑制导致神经炎症减少，神经行为缺陷减轻，TBI 后很长时间内组织损失减少。这些临床前发现表明，IFN-β 可能是 TBI 的潜在治疗靶点。
