Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury.
Targeting the thrombin receptor modulates inflammation and astrogliosis to improve recovery after spinal cord injury.
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DOI：
10.1016/j.nbd.2016.04.010
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发表时间：
2016-09
影响因子：
6.1
通讯作者：
Scarisbrick IA
中科院分区：
文献类型：
--
作者：
Radulovic M;Yoon H;Wu J;Mustafa K;Scarisbrick IA
丝氨酸蛋白酶活性的失调是神经损伤的共同特征，但对其作用机制或是否可以靶向促进修复知之甚少。在这项研究中，我们证明了凝血酶受体（蛋白酶激活受体1，PAR1）作为一个关键的翻译，将脊髓损伤（SCI）蛋白水解微环境转化为一系列促炎事件，导致星形胶质细胞形成和功能下降。PAR1敲除小鼠在脊髓损伤后表现出更好的运动恢复，炎症和星形胶质形成的特征减少，包括胶质纤维酸性蛋白（GFAP）、vimentin和STAT3信号的表达。在PAR1−/−小鼠中，sci相关的促炎细胞因子如IL-1β和IL-6的升高也降低，并且观察到neun阳性的腹角神经元和PKCγ皮质脊髓轴突的组织保留和保存的协调改善。PAR1及其激动剂的凝血酶和神经素在病变周围星形胶质细胞中表达，每种激动剂都以PAR1依赖的方式增加原代星形胶质细胞培养中IL-6和STAT3信号的产生。反过来，il -6刺激的星形胶质细胞增加了PAR1、凝血酶和神经素的表达，这表明PAR1激活通过前驱和反馈信号动力学促进星形胶质细胞增生的模型。总的来说，这些发现确定凝血酶受体是脊髓损伤后炎症和星形胶质细胞形成的关键介质，可以靶向减少神经退行性变和改善神经行为恢复。
The deregulation of serine protease activity is a common feature of neurological injury, but little is known regarding their mechanisms of action or whether they can be targeted to facilitate repair. In this study we demonstrate that the thrombin receptor (Protease Activated Receptor 1, (PAR1)) serves as a critical translator of the spinal cord injury (SCI) proteolytic microenvironment into a cascade of pro-inflammatory events that contribute to astrogliosis and functional decline. PAR1 knockout mice displayed improved locomotor recovery after SCI and reduced signatures of inflammation and astrogliosis, including expression of glial fibrillary acidic protein (GFAP), vimentin, and STAT3 signaling. SCI-associated elevations in pro-inflammatory cytokines such as IL-1β and IL-6 were also reduced in PAR1−/− mice and co-ordinate improvements in tissue sparing and preservation of NeuN-positive ventral horn neurons, and PKCγ corticospinal axons, were observed. PAR1 and its agonist’s thrombin and neurosin were expressed by perilesional astrocytes and each agonist increased the production of IL-6 and STAT3 signaling in primary astrocyte cultures in a PAR1-dependent manner. In turn, IL-6-stimulated astrocytes increased expression of PAR1, thrombin, and neurosin, pointing to a model in which PAR1 activation contributes to increased astrogliosis by feedforward- and feedback-signaling dynamics. Collectively, these findings identify the thrombin receptor as a key mediator of inflammation and astrogliosis in the aftermath of SCI that can be targeted to reduce neurodegeneration and improve neurobehavioral recovery.