Strain influences on inflammatory pathway activation, cell infiltration and complement cascade after traumatic brain injury in the rat
Strain influences on inflammatory pathway activation, cell infiltration and complement cascade after traumatic brain injury in the rat
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DOI：
10.1016/j.bbi.2012.10.002
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发表时间：
2013-01-01
影响因子：
15.1
通讯作者：
Piehl, Fredrik
中科院分区：
文献类型：
--
作者：
Al Nimer, Faiez;Lindblom, Rickard;Piehl, Fredrik
越来越多的证据表明，遗传背景影响创伤性脑损伤（TB！）的结果。然而，关于遗传异质性影响哪些途径/过程的详细知识仍然有限。近交系大鼠品系DA和PVC在TBI后的神经元存活方面不同。我们在这里进行了全球表达谱，以确定差异调节的途径，控制实验性脑挫伤损伤的反应。其中一个差异最大的调节分子网络涉及免疫细胞运输。随后使用流式细胞术对所涉及的细胞进行表征，结果表明与PVG大鼠相比，DA中的中性粒细胞和单核细胞浸润更大，小胶质细胞活化程度更高。此外，与CD 161 dim NK细胞相比，DA大鼠显示出更高数量的NK细胞和更高比例的CD 161 bright。补体途径分子如C1和C3在DA中的局部表达较高，并且关键补体组分C3和膜攻击复合物（MAC）都可以在轴突和神经细胞上被证明。DA中补体系统的较强激活与脑脊液中神经递质-光（神经/轴突损伤的生物标志物）的较高水平相关。总之，我们证明了DA和PVC大鼠在炎症通路激活方面的实质性差异;特别是TBI后与神经元/轴突损伤相关的免疫细胞流入和补体激活。这些研究结果表明，遗传影响炎症激活是重要的TBI和激励进一步努力使用实验正向遗传学，以确定影响结果的基因/途径。(C)2012 Elsevier Inc. All rights reserved.
Increasing evidence suggests that genetic background affects outcome of traumatic brain injuries (TB!). Still, there is limited detailed knowledge on what pathways/processes are affected by genetic heterogeneity. The inbred rat strains DA and PVC differ in neuronal survival following TBI. We here carried out global expressional profiling to identify differentially regulated pathways governing the response to an experimental controlled brain contusion injury. One of the most differentially regulated molecular networks concerned immune cell trafficking. Subsequent characterization of the involved cells using flow cytometry demonstrated greater infiltration of neutrophils and monocytes, as well as a higher degree of microglia activation in DA compared to PVG rats. In addition, DA rats displayed a higher number of NK cells and a higher ratio of CD161bright compared to CD161dim NK cells. Local expression of complement pathway molecules such as Cl and C3 was higher in DA and both the key complement component C3 and membrane-attack complex (MAC) could be demonstrated on axons and nerve cells. A stronger activation of the complement system in DA was associated with higher cerebrospinal fluid levels of neurofilament-light, a biomarker for nerve/axonal injury. In summary, we demonstrate substantial differences between DA and PVC rats in activation of inflammatory pathways; in particular, immune cell influx and complement activation associated with neuronal/axonal injury after TBI. These findings suggest genetic influences acting on inflammatory activation to be of importance in TBI and motivate further efforts using experimental forward genetics to identify genes/pathways that affect outcome. (C) 2012 Elsevier Inc. All rights reserved.