Kwan Thaddaeus, Floyd Candace L, Patel Jason, Mohaimany-Aponte Amanda, King Peter H
Department of Neurology, University of Alabama, Room 545 Civitan Building, 7th Ave South, Birmingham, AL 35233-0017, United States.
Department of Physical Medicine and Rehabilitation, University of Alabama, Rm SRC 529c, 1717 6th Ave South, Birmingham, AL 35249, United States.
Neurosci Lett. 2017 Jun 9;651:140-145. doi: 10.1016/j.neulet.2017.05.003. Epub 2017 May 6.
We recently showed that the RNA regulator, HuR, is translocated to the cytoplasm in astrocytes in the acute phase of spinal cord injury (SCI), consistent with its activation. HuR positively modulates expression of many pro-inflammatory factors, including IL-1β, TNF-α, and MMP-12, which are present at high levels in the early phase of SCI and exacerbate tissue damage. Knockdown of HuR in astrocytes blunts expression of these factors in an in vitro stretch injury model of CNS trauma. In this report, we further investigate the impact of HuR in early SCI using a mouse model in which human HuR is transgenically expressed in astrocytes. At 24h following a mid-thoracic contusion injury, transgenic HuR translocated to the cytoplasm of astrocytes, similar to endogenous HuR, and consistent with its activation. Compared to littermate controls, the transgenic mice showed a global increase in astrocyte activation at the level of injury and a concomitant increase in vascular permeability. There was a significant decrease in neuronal survival at this time interval, but no differences in white matter sparing. Long term behavioral assessments showed no difference in motor recovery. In summary, transgenic expression of HuR in astrocytes accentuated neuronal injury and other secondary features of SCI including increased vascular permeability and astrocyte activation. These findings underscore HuR as a potential therapeutic target in early SCI.
我们最近发现，RNA调节因子HuR在脊髓损伤（SCI）急性期的星形胶质细胞中易位至细胞质，这与其激活状态相符。HuR正向调节许多促炎因子的表达，包括IL-1β、TNF-α和MMP-12，这些因子在SCI早期水平较高，并加剧组织损伤。在中枢神经系统创伤的体外拉伸损伤模型中，敲低星形胶质细胞中的HuR可减弱这些因子的表达。在本报告中，我们使用一种在星形胶质细胞中转基因表达人HuR的小鼠模型，进一步研究HuR在早期SCI中的作用。在胸段中部挫伤损伤后24小时，转基因HuR易位至星形胶质细胞的细胞质，与内源性HuR相似，这与其激活状态相符。与同窝对照相比，转基因小鼠在损伤水平处星形胶质细胞的整体激活增加，同时血管通透性增加。在此时间间隔内，神经元存活率显著降低，但白质保留无差异。长期行为评估显示运动恢复无差异。总之，星形胶质细胞中HuR的转基因表达加剧了神经元损伤以及SCI的其他继发性特征，包括血管通透性增加和星形胶质细胞激活。这些发现强调HuR是早期SCI潜在的治疗靶点。
