hold postdoctoral fellowships from FCT (FRH/BPD/91962/2012 and SFRH/BPD/91833/2012, respectively). is a research fellow from CNPq and Faperj (Brazil). Funding: FEDER and FCT, Portugal, supported work in J.B.R.’s laboratory. Sampaio for advice on confocal microscopy and image analysis. Overall, our work demonstrates the importance of the ascorbate transport system for microglial homeostasis and hints that dysregulation of ascorbate transport might play a role in neurological disorders. Ascorbate treatment, SVCT2 overexpression, or blocking SVCT2 internalization prevented the activation of microglia. Src-mediated phosphorylation of caveolin-1 on Tyr 14 in microglia induced the internalization of SVCT2. We found that depletion of SVCT2 from the plasma membrane triggered a proinflammatory phenotype in microglia and resulted in microglia activation. We demonstrated that ascorbate uptake through SVCT2 was critical for the homeostasis of microglia, the resident myeloid cells of the CNS that are essential for proper functioning of the nervous tissue. SVCT2 specifically transports ascorbate, the reduced form of vitamin C, which acts as a reducing agent. The plasma membrane sodium–vitamin C cotransporter 2 (SVCT2) is the primary mediator of vitamin C uptake in neurons. Vitamin C is essential for the development and function of the central nervous system (CNS).
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