title: Caveolin-1-mediated internalization of the vitamin C transporter SVCT2 in microglia triggers an inflammatory phenotype.
abstract: 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 Tyr14in 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.
authors.affiliation: Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208 4200-135 Porto, Portugal. jrelvas@ibmc.up.pt camila.portugal@ibmc.up.pt.
authors.forename: Camila C
authors.identifier: http://orcid.org/0000-0002-1093-6545
authors.initials: CC
authors.lastname: Portugal
authors.affiliation: Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208 4200-135 Porto, Portugal.
authors.forename: Renato
authors.identifier: http://orcid.org/0000-0002-6882-5020
authors.initials: R
authors.lastname: Socodato
authors.affiliation: Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208 4200-135 Porto, Portugal.
authors.forename: Teresa
authors.identifier: http://orcid.org/0000-0002-4000-153X
authors.initials: T
authors.lastname: Canedo
authors.affiliation: Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208 4200-135 Porto, Portugal.
authors.forename: Cátia M
authors.initials: CM
authors.lastname: Silva
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Health Sciences Campus, Azinhaga Santa Comba, 3000-548 Coimbra, Portugal.|Center for Neuroscience and Cell Biology, Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Consortium, University of Coimbra, Coimbra, Portugal.
authors.forename: Tânia
authors.initials: T
authors.lastname: Martins
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Health Sciences Campus, Azinhaga Santa Comba, 3000-548 Coimbra, Portugal.|Department of Neurobiology and Program of Neurosciences, Institute of Biology, Fluminense Federal University, Rua Outeiro São João Batista, 24020-971 Niterói, Rio de Janeiro, Brazil.
authors.forename: Vivian S M
authors.identifier: http://orcid.org/0000-0002-8604-7891
authors.initials: VS
authors.lastname: Coreixas
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Health Sciences Campus, Azinhaga Santa Comba, 3000-548 Coimbra, Portugal.|Department of Neurobiology and Program of Neurosciences, Institute of Biology, Fluminense Federal University, Rua Outeiro São João Batista, 24020-971 Niterói, Rio de Janeiro, Brazil.
authors.forename: Erick C
authors.identifier: http://orcid.org/0000-0002-7926-795X
authors.initials: EC
authors.lastname: Loiola
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany.|Department of Neurology, RWTH Aachen University, Pauwelstrasse 30, 52074 Aachen, Germany.
authors.forename: Burkhard
authors.identifier: http://orcid.org/0000-0002-2594-8557
authors.initials: B
authors.lastname: Gess
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Röhr
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Health Sciences Campus, Azinhaga Santa Comba, 3000-548 Coimbra, Portugal.|Center for Neuroscience and Cell Biology, Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Consortium, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana R
authors.identifier: http://orcid.org/0000-0002-7541-7041
authors.initials: AR
authors.lastname: Santiago
authors.affiliation: Department of Neurology, University of Muenster, 48149 Muenster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Young
authors.affiliation: Department of Pharmacology and Center for Lung and Vascular Biology and Department of Anesthesiology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Richard D
authors.identifier: http://orcid.org/0000-0003-3164-475X
authors.initials: RD
authors.lastname: Minshall
authors.affiliation: Department of Neurobiology and Program of Neurosciences, Institute of Biology, Fluminense Federal University, Rua Outeiro São João Batista, 24020-971 Niterói, Rio de Janeiro, Brazil.
authors.forename: Roberto
authors.identifier: http://orcid.org/0000-0002-4081-7547
authors.initials: R
authors.lastname: Paes-de-Carvalho
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Health Sciences Campus, Azinhaga Santa Comba, 3000-548 Coimbra, Portugal.|Center for Neuroscience and Cell Biology, Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Consortium, University of Coimbra, Coimbra, Portugal.
authors.forename: António F
authors.identifier: http://orcid.org/0000-0002-0477-1641
authors.initials: AF
authors.lastname: Ambrósio
authors.affiliation: Instituto de Investigação e Inovação em Saúde and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Rua Alfredo Allen, 208 4200-135 Porto, Portugal. jrelvas@ibmc.up.pt camila.portugal@ibmc.up.pt.
authors.forename: João B
authors.identifier: http://orcid.org/0000-0001-7636-0924
authors.initials: JB
authors.lastname: Relvas
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism*; D015153:Blotting, Western; D051242:Caveolin 1 / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004705:Endocytosis; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D017208:Rats, Wistar; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D016207:Cytokines; D018836:Inflammation Mediators; D060347:Sodium-Coupled Vitamin C Transporters; D001205:Ascorbic Acid