Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake

Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium-dependent vitamin C transporter-2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS-induced tumor necrosis factor- α (TNF α ) are increased. Elevated levels of LPS and TNF α have been associated with neurodegenerative diseases together with reduced levels of AA. However, little is known about the impacts of LPS and TNF α on neuronal AA uptake. The objective of this study was to examine the effect of LPS and TNF α on SVCT2 expression and function using in vitro and in vivo approaches. Treatment of SH-SY5Y cells with either LPS or TNF α inhibited AA uptake. This reduced uptake was associated with a significant decrease in SVCT2 protein and mRNA levels. In vivo exposure to LPS or TNF α also decreased SVCT2 protein and mRNA levels in mouse brains. Both LPS and TNF α decreased SLC23A2 promoter activity. Further, the inhibitory effect of LPS on a minimal SLC23A2 promoter was attenuated when either the binding site for the transcription factor Sp1 was mutated or cells were treated with the NF- κ B inhibitor, celastrol. We conclude that inflammatory signals suppress AA uptake by impairing SLC23A2 transcription through opposing regulation of Sp1 and NF- κ B factors.