Wittmann Gábor, Mohácsik Petra, Balkhi Mumtaz Yaseen, Gereben Balázs, Lechan Ronald M
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Tupper Research Institute, Tufts Medical Center, Boston, MA, USA.
Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
Fluids Barriers CNS. 2015 Sep 4;12:21. doi: 10.1186/s12987-015-0016-8.
We recently reported that bacterial lipopolysaccharide (LPS)-induced inflammation decreases the expression of the primary thyroid hormone transporters at the blood-brain barrier, organic anion-transporting polypeptide 1c1 (OATP1c1) and monocarboxylate transporter 8 (MCT8). L-type amino acid transporters 1 and 2 (LAT1 & LAT2) are regarded as secondary thyroid hormone transporters, and are expressed in cells of the blood-brain or blood-cerebrospinal fluid barrier and by neurons. The purpose of this study was to examine the effect of LPS-induced inflammation on the expression of LAT1 and LAT2, as these may compensate for the downregulation of OATP1c1 and MCT8.
LPS (2.5 mg/kg body weight) was injected intraperitoneally to adult, male, Sprague-Dawley rats and C57Bl/6 mice, which were euthanized 2, 4, 9, 24 or 48 h later. LAT1 and LAT2 mRNA expression were studied on forebrain sections using semiquantitative radioactive in situ hybridization. LAT1 protein levels in brain vessels were studied using LAT1 immunofluorescence. Statistical comparisons were made by the non-parametric Kruskal-Wallis and Dunn's tests.
In both species, LAT1 mRNA decreased in brain blood vessels as soon as 2 h after LPS injection and was virtually undetectable at 4 h and 9 h. During recovery from endotoxemia, 48 h after LPS injection, LAT1 mRNA in brain vessels increased above control levels. A modest but significant decrease in LAT1 protein levels was detected in the brain vessels of mice at 24 h following LPS injection. LPS did not affect LAT1 and LAT2 mRNA expression in neurons and choroid plexus epithelial cells.
The results demonstrate that LPS-induced inflammation rapidly decreases LAT1 mRNA expression at the blood-brain barrier in a very similar manner to primary thyroid hormone transporters, while changes in LAT1 protein level follow a slower kinetics. The data raise the possibility that inflammation may similarly down-regulate other blood-brain barrier transport systems at the transcriptional level. Future studies are required to examine this possibility and the potential pathophysiological consequences of inflammation-induced changes in blood-brain barrier transport functions.
我们最近报道，细菌脂多糖（LPS）诱导的炎症会降低血脑屏障处主要甲状腺激素转运体——有机阴离子转运多肽1c1（OATP1c1）和单羧酸转运体8（MCT8）的表达。L型氨基酸转运体1和2（LAT1和LAT2）被视为次要甲状腺激素转运体，在血脑屏障或血脑脊液屏障的细胞以及神经元中表达。本研究的目的是检测LPS诱导的炎症对LAT1和LAT2表达的影响，因为它们可能会补偿OATP1c1和MCT8的下调。
将LPS（2.5mg/kg体重）腹腔注射到成年雄性Sprague-Dawley大鼠和C57Bl/6小鼠体内，在注射后2、4、9、24或48小时对其实施安乐死。使用半定量放射性原位杂交技术研究前脑切片中LAT1和LAT2 mRNA的表达。使用LAT1免疫荧光技术研究脑血管中LAT1蛋白水平。通过非参数Kruskal-Wallis检验和Dunn检验进行统计学比较。
在这两个物种中，LPS注射后2小时，脑血管中的LAT1 mRNA就开始下降，在4小时和9小时几乎检测不到。在内毒素血症恢复期间，即LPS注射后48小时，脑血管中的LAT1 mRNA增加至高于对照水平。在LPS注射后24小时，在小鼠脑血管中检测到LAT1蛋白水平有适度但显著的下降。LPS不影响神经元和脉络丛上皮细胞中LAT1和LAT2 mRNA的表达。
结果表明，LPS诱导的炎症以与主要甲状腺激素转运体非常相似的方式迅速降低血脑屏障处的LAT1 mRNA表达，而LAT1蛋白水平的变化动力学较慢。这些数据增加了炎症可能在转录水平上类似地下调其他血脑屏障转运系统的可能性。需要进一步的研究来检验这种可能性以及炎症诱导的血脑屏障转运功能变化的潜在病理生理后果。
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