Inhibition of System Xc- Transporter Attenuates Autoimmune Inflammatory XXXX .

@entity32 @entity17 @entity3026 @entity3264 @entity19 @entity20568 @entity6503
UNASSIGNED: T cell infiltration into the CNS is a significant underlying pathogenesis in @entity3026 . Several lines of evidence suggest that @entity3264 dysregulation in the CNS is an important consequence of immune cell infiltration in neuroinflammatory @entity17 ; yet, the causal link between @entity32 and @entity3264 dysregulation is not well understood. A major source of @entity3264 release during oxidative stress is the system Xc (-) transporter; however, this mechanism has not been tested in animal models of @entity3026 . We find that pharmacological and genetic inhibition of system Xc (-) attenuates chronic and relapsing-remitting @entity6503 ( @entity6503 ). Remarkably, pharmacological blockade of system Xc (-) 7 d after induction of @entity6503 attenuated T cell infiltration into the CNS, but not T cell activation in the periphery. @entity19 harboring a @entity20568 ( @entity20568 ) mutation that inactivated system Xc (-) were resistant to @entity6503 , 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 @entity6503 abrogated clinical disease, @entity32 , and myelin loss. Primary coculture studies demonstrate that myelin-specific CD4(+) Th1 cells provoke microglia to release @entity3264 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 @entity17 after immune cell infiltration in @entity6503 .
