Abstract
BackgroundWe 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.MethodsLPS (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.ResultsIn 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12987-015-0016-8) contains supplementary material, which is available to authorized users.
Highlights
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 & l-type amino acid transporter 2 (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
To determine whether upregulation of l-type amino acid transporter 1 (LAT1) and LAT2 compensates for the downregulation of MCT8 and OATP1c1 during inflammation and offsets the effect of reduced brain thyroid hormone (TH) uptake on neurons, we examined the effect of LPS on LAT1 and LAT2 expression in the mouse and rat forebrain using in situ hybridization to study LAT1 and LAT2 mRNAs in a cell-type specific-manner, as well as immunofluorescence to study LAT1 protein levels
Neuronal LAT1 hybridization was more prominent in most hypothalamic nuclei, the medial habenular nucleus of the thalamus, certain amygdalar regions, hippocampal principal cell layers and pyriform cortex, whereas only light signal labeled most of the cortical areas and several thalamic nuclei (Fig. 2A)
Summary
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. 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). We recently described that during systemic inflammation induced by bacterial lipopolysaccharide (LPS) administration, OATP1c1 and MCT8 mRNAs, as well as OATP1c1 protein markedly decrease in brain vessels [10]. The downregulation of these transporters at the blood–brain barrier would suggest reduced TH uptake into the brain and lower brain TH concentration, especially during prolonged systemic inflammatory states. LAT1 and LAT2 may contribute to TH transport across the blood–brain and blood-cerebrospinal fluid barriers and facilitate neuronal uptake and/or release of TH
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