Effect of Stress and Peripheral Immune Activation on Astrocyte Activation in Transgenic Bioluminescent Gfap-luc Mice
Effect of Stress and Peripheral Immune Activation on Astrocyte Activation in Transgenic Bioluminescent Gfap-luc Mice
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DOI：
10.1002/glia.22804
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发表时间：
2015-07-01
期刊：
影响因子：
6.2
通讯作者：
Nuydens, Rony
中科院分区：
文献类型：
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作者：
Biesmans, Steven;Acton, Paul D.;Nuydens, Rony
神经炎症和伴随的神经胶质细胞激活是许多神经退行性疾病的重要特征。众所周知，外周感染和压力等因素会影响大脑的免疫过程。然而，这些应激源对体内星形胶质细胞激活的影响仍然难以捉摸。在这项研究中，转基因 Gfap-luc 小鼠在神经胶质原纤维酸性蛋白启动子的转录控制下表达荧光素酶基因，用于量化与临床炎症相关的免疫挑战后体内星形胶质细胞激活的动力学。研究发现，星形胶质细胞对细菌脂多糖（LPS）或病毒模拟物聚肌胞：聚胞苷酸（poly（I：C））引起的外周免疫激活做出快速反应。通过测量同一动物的生物发光和 18-kDa 易位蛋白放射性配体结合，观察到 LPS 在给药后 6 小时诱导星形胶质细胞和小胶质细胞活化。此外，星形胶质细胞的反应在重复全身性LPS注射后下降，表明对LPS挑战的耐受性的发展。最后，连续5天每天限制Gfap-luc小鼠1小时不会影响大脑生物发光，从而表明亚慢性应激在未受到挑战的条件下不会影响星形胶质细胞的激活。然而，应激动物对随后的全身LPS注射的反应减弱，表明这些动物的免疫系统受到损害。在这里，我们证明 Gfap-luc 小鼠可用于研究星形胶质细胞对临床炎症相关刺激的激活反应，并且这种方法可以为现有和新型神经炎症模型提供更完整的表征。 GLIA 2015；63：1126-1137
Neuroinflammation and the accompanying activation of glial cells is an important feature of many neurodegenerative conditions. It is known that factors such as peripheral infections and stress can influence immune processes in the brain. However, the effect of these stressors on astrocyte activation in vivo remains elusive. In this study, transgenic Gfap-luc mice expressing the luciferase gene under the transcriptional control of the glial fibrillary acidic protein promoter were used to quantify the kinetics of in vivo astrocyte activation following immune challenges relevant to clinical inflammation. It was found that astrocytes respond rapidly to peripheral immune activation elicited by either bacterial lipopolysaccharide (LPS) or the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)). By measuring bioluminescence and 18-kDa translocator protein radioligand binding in the same animal it was observed that LPS induces both astrocyte as well as microglial activation at 6 h post-administration. Furthermore, the astrocyte response decreased upon repeated systemic LPS injections, indicating development of tolerance to the LPS challenge. Finally, restraining Gfap-luc mice for 1 h daily on 5 consecutive days did not affect brain bioluminescence, thereby indicating that sub-chronic stress does not influence astrocyte activation under unchallenged conditions. However, stressed animals showed a reduced response to a subsequent systemic LPS injection, suggesting that the immune system is compromised in these animals. Here, we demonstrate that Gfap-luc mice can be used to study astrocyte activation in response to stimuli relevant for clinical inflammation and that this approach may provide a more complete characterization of existing and novel models of neuroinflammation. GLIA 2015;63:1126-1137