Abstract
BackgroundLipopolysaccharide (LPS) is one of the main constituents of the cell wall of gram-negative bacteria. As an endotoxin, LPS induces neuroinflammation, which is associated with the blood-brain barrier impairment. Lactate is a metabolite with some significant physiological functions within the neurovascular unit/blood-brain barrier (BBB). Accumulation of extracellular and cerebrospinal fluid lactate is a specific feature of bacterial meningitis. However, the role of lactate production, transport, and sensing by lactate receptors GPR81 in the pathogenesis of bacterial neuroinflammation is still unknown.MethodsIn this study, we analyzed effects of LPS on the expression of GPR81 and MCT-1 and proliferation of cerebral endothelial cells in the BBB model in vitro. We used molecular profiling methods to measure the expression of GPR81, MCT-1, IL-1β, and Ki67 in the cerebral endothelium after treatment with different concentrations of LPS followed by measuring the level of extracellular lactate, transendothelial electric resistance, and permeability of the endothelial cell layer.ResultsOur findings showed that exposure to LPS results in neuroinflammatory changes associated with decreased expression of GPR81 and MCT-1 in endothelial cells, as well as overproduction of IL-1β and elevation of lactate concentrations in the extracellular space in a dose-dependent manner. LPS treatment reduced JAM tight junction protein expression in cerebral endothelial cells and altered BBB structural integrity in vitro.ConclusionThe impairment of lactate reception and transport might contribute to the alterations of BBB structural and functional integrity caused by LPS-mediated neuroinflammation.
Highlights
Bacterial meningitis is a life-threatening disease of the central nervous system (CNS), in children
In vitro exposure of rat blood-brain barrier (BBB) model to LPS in two tested concentrations during 24 h resulted in a progressive decrease of Transendothelial electric resistance (TEER) and elevated permeability of the barrier in Lucifer yellow (LY)-test (Fig. 1a, b)
Incubation of brain microvessel endothelial cells (BMECs) with LPS exhibited a reduction in G protein-coupled receptor 81 (GPR81) expression after 24 h of incubation with no clear difference between two tested LPS concentrations (Fig. 2a)
Summary
Bacterial meningitis is a life-threatening disease of the central nervous system (CNS), in children. Bacterial meningitis is recognized as the main cause of the top ten infection-associated death worldwide [1, 2]. Several pathogenic mechanisms lead to the development of brain injury in bacterial meningitis, including leukocyte transmigration and microglia activation. Such events cause cytotoxicity, neuronal cell death, and local production of pro-inflammatory cytokines and chemokines. Neuronal cell death, and local production of pro-inflammatory cytokines and chemokines Overall, these effects lead to acute neuroinflammation, remodeling of extracellular matrix, BBB breakdown, and progression of neurological deficits [10, 11]. LPS induces neuroinflammation, which is associated with the blood-brain barrier impairment. The role of lactate production, transport, and sensing by lactate receptors GPR81 in the pathogenesis of bacterial neuroinflammation is still unknown
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