Research ArticleNeuroscience

Caveolin-1–mediated internalization of the vitamin C transporter SVCT2 in microglia triggers an inflammatory phenotype

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Science Signaling  28 Mar 2017:
Vol. 10, Issue 472, eaal2005
DOI: 10.1126/scisignal.aal2005

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Vitamin C prevents microglia activation

Changes in the abundance of ascorbate, the reduced form of vitamin C, in the central nervous system (CNS) alter neuronal function and are associated with neurodevelopmental and neurodegenerative disorders. Activation of microglia, which occurs in response to tissue damage or pathogens, also contributes to neurodegenerative disease. Portugal et al. showed that the plasma membrane sodium–vitamin C cotransporter 2 (SVCT2) was required for microglia homeostasis in the CNS. Decreasing the amount of SVCT2 in the plasma membrane reduced vitamin C uptake and triggered activation of both primary rodent and human microglia. Treating microglia with ascorbate or preventing the internalization of SVCT2 blocked activation of microglia. These results demonstrate that ascorbate plays an essential role in microglial homeostasis and may prevent the microglial activation that contributes to neurodegenerative disease.


Vitamin C is essential for the development and function of the central nervous system (CNS). The plasma membrane sodium–vitamin C cotransporter 2 (SVCT2) is the primary mediator of vitamin C uptake in neurons. SVCT2 specifically transports ascorbate, the reduced form of vitamin C, which acts as a reducing agent. 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. We found that depletion of SVCT2 from the plasma membrane triggered a proinflammatory phenotype in microglia and resulted in microglia activation. Src-mediated phosphorylation of caveolin-1 on Tyr14 in microglia induced the internalization of SVCT2. Ascorbate treatment, SVCT2 overexpression, or blocking SVCT2 internalization prevented the activation of microglia. 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.

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