Microglial activation and responses to vasculature that result from an acute LPS exposure
Microglial activation and responses to vasculature that result from an acute LPS exposure
复制标题
DOI：
10.1016/j.neuro.2020.01.014
复制
发表时间：
2020-03-01
期刊：
影响因子：
3.4
通讯作者：
Hanig, Joseph P.
中科院分区：
文献类型：
--
作者：
Bowyer, John F.;Sarkar, Sumit;Hanig, Joseph P.
细菌细胞壁内毒素，即脂多糖（LPS），是一些显示可引起全身炎症/先天性免疫应答和神经炎症的典型体征的原始化合物。术语神经炎症通常用于推断由神经元靶向活性引起的小胶质细胞对促炎介质的加工。然而，小胶质细胞也可能通过几种信号传导机制对血管系统做出反应。在急性暴露于单次皮下注射2 mg/kg LPS后，测定海马和顶叶皮质中相对于脉管系统的小胶质细胞活化。同种异体移植物炎性因子（Aifl，a.k.a. Ibal）用于追踪和量化小胶质细胞的形态学变化。血小板/内皮细胞粘附分子1（Pecaml，a.k.a. Cd 31）用于显示前脑中的脉管系统，胶质酸性胶质细胞蛋白（GFAP）用于显示星形胶质细胞。在LPS暴露后3 h、6 h、12 h、24 h、3 d和14 d，对神经炎症和神经毒性的其他方面进行组织学评价。FluoroJadeC标记表明LPS不引起神经变性。此外，没有由于LPS导致的小鼠IgG从脑血管系统渗漏的迹象。小胶质细胞的大小在6小时发生了一些变化，但到12小时，小胶质细胞的激活已经开始与组合的索马和近端突起的大小显着增加（1.5倍）。在24小时，几乎所有的小胶质细胞索马和近端的海马，顶叶皮质和丘脑的过程中密切相关的血管，并增加了近2.0倍的大小。在小胶质细胞与血管并列的许多区域，星形胶质细胞的终足似乎被移位。小胶质细胞的激活略有下降，3天的小胶质细胞的大小为对照组的1.6倍。我们假设急性LPS激活可通过以下几种机制导致血管介导的小胶质细胞反应：1）与位于血管系统上的小胶质细胞过程上的Cd 14和TIr 4受体结合; 2）损伤血管系统并导致细胞因子释放; 3）可能导致细胞因子释放的星形胶质细胞终足损伤。这些急性反应可能是暴露于循环LPS的适应机制，其中小胶质细胞包围血管系统。这可以进一步防止血液中循环的病原体进入大脑。然而，将小胶质细胞的相互作用从突触重塑和其它类型的小胶质细胞与神经元的相互作用转移开可能对神经元功能具有不利影响。
Bacterial cell wall endotoxins, i.e. lipopolysaccharides (LPS), are some of the original compounds shown to evoke the classic signs of systemic inflammation/innate immune response and neuroinflammation. The term neuroinflammation often is used to infer the elaboration of proinflammatory mediators by microglia elicited by neuronal targeted activity. However, it also is possible that the microglia are responding to vasculature through several signaling mechanisms. Microglial activation relative to the vasculature in the hippocampus and parietal cortex was determined after an acute exposure of a single subcutaneous injection of 2 mg/kg LPS. Antibodies to allograft inflammatory factor (Aifl, a.k.a. Ibal) were used to track and quantify morphological changes in microglia. Immunostaining of platelet/endothelial cell adhesion molecule 1 (Pecaml, a.k.a. Cd31) was used to visualize vasculature in the forebrain and glial acidic fibrillary protein (GFAP) to visualize astrocytes. Neuroinflammation and other aspects of neurotoxicity were evaluated histologically at 3 h, 6 h, 12 h, 24 h, 3 d and 14 d following LPS exposure. LPS did not cause neurodegeneration as determined by Fluoro Jade C labeling. Also, there were no signs of mouse IgG leakage from brain vasculature due to LPS. Some changes in microglia size occurred at 6 h, but by 12 h microglial activation had begun with the combined soma and proximal processes size increasing significantly (1.5-fold). At 24 h, almost all the microglia soma and proximal processes in the hippocampus, parietal cortex, and thalamus were closely associated with the vasculature and had increased almost 2.0-fold in size. In many areas where microglia were juxtaposed to vasculature, astrocytic endfeet appeared to be displaced. The microglial activation had subsided slightly by 3 d with microglial size 1.6-fold that of control. We hypothesize that acute LPS activation can result in vascular mediated microglial responses through several mechanisms: 1) binding to Cd14 and TIr4 receptors on microglia processes residing on vasculature; 2) damaging vasculature and causing the release of cytokines; and 3) possibly astrocytic endfeet damage resulting in cytokine release. These acute responses may serve as an adaptive mechanism to exposure to circulating LPS where the microglia surround the vasculature. This could further prevent the pathogen(s) circulating in blood from entering the brain. However, diverting microglial interactions away from synaptic remodeling and other types of microglial interactions with neurons may have adverse effects on neuronal function.