title: Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination.
abstract: T cell infiltration into the CNS is a significant underlying pathogenesis in autoimmune inflammatory demyelinating diseases. Several lines of evidence suggest that glutamate dysregulation in the CNS is an important consequence of immune cell infiltration in neuroinflammatory demyelinating diseases; yet, the causal link between inflammation and glutamate dysregulation is not well understood. A major source of glutamate release during oxidative stress is the system Xc(-) transporter; however, this mechanism has not been tested in animal models of autoimmune inflammatory demyelination. We find that pharmacological and genetic inhibition of system Xc(-) attenuates chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE). Remarkably, pharmacological blockade of system Xc(-) 7 d after induction of EAE attenuated T cell infiltration into the CNS, but not T cell activation in the periphery. Mice harboring a Slc7a11 (xCT) mutation that inactivated system Xc(-) were resistant to EAE, corroborating a central role for system Xc(-) in mediating immune cell infiltration. We next examined the role of the system Xc(-) transporter in the CNS after immune cell infiltration. Pharmacological inhibitors of the system Xc(-) transporter administered during the first relapse in a SJL animal model of relapsing-remitting EAE abrogated clinical disease, inflammation, and myelin loss. Primary coculture studies demonstrate that myelin-specific CD4(+) Th1 cells provoke microglia to release glutamate via the system Xc(-) transporter, causing excitotoxic death to mature myelin-producing oligodendrocytes. Taken together, these studies support a novel role for the system Xc(-) transporter in mediating T cell infiltration into the CNS as well as promoting myelin destruction after immune cell infiltration in EAE.
authors.affiliation: Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294.|Department of Physical Medicine Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, 35294.
authors.forename: Kirsten S
authors.initials: KS
authors.lastname: Evonuk
authors.affiliation: Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294.|Department of Physical Medicine Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, 35294.
authors.forename: Brandi J
authors.initials: BJ
authors.lastname: Baker
authors.affiliation: Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294.|Department of Physical Medicine Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, 35294.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Doyle
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, AL, 35294.
authors.forename: Carson E
authors.initials: CE
authors.lastname: Moseley
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294.|Department of Biology, Chemistry, and Mathematics, University of Montevallo, Montevallo, AL 35115.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Sestero
authors.affiliation: Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294.|Department of Physical Medicine Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, 35294.
authors.forename: Bryce P
authors.initials: BP
authors.lastname: Johnston
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294.
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Sarno
authors.affiliation: Department of Physical Medicine Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, 35294.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tang
authors.affiliation: Department of Physical Medicine Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, 35294.
authors.forename: Igor
authors.initials: I
authors.lastname: Gembitsky
authors.affiliation: Department of Biology, Program in Neuroscience, Syracuse University, Syracuse, NY, 13244.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hewett
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, AL, 35294.
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294.
authors.forename: Chander
authors.initials: C
authors.lastname: Raman
authors.affiliation: Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294.|Department of Physical Medicine Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, 35294.|Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294.
authors.forename: Tara M
authors.initials: TM
authors.lastname: DeSilva
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D001565:Benzoates / Q000494:pharmacology*; D002465:Cell Movement; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D015870:Gene Expression; D005973:Glutamine / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009186:Myelin Sheath / Q000235:genetics / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009836:Oligodendroglia / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D061251:Primary Cell Culture; D051381:Rats; D020318:Rats, Long-Evans; D012460:Sulfasalazine / Q000494:pharmacology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D027182:Amino Acid Transport System y+; D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D063308:Myelin-Oligodendrocyte Glycoprotein; C492255:Slc7a11 protein, mouse; D005973:Glutamine; D012460:Sulfasalazine; C079693:4-carboxyphenylglycine; D005998:Glycine