Tara DeSilva
University of Alabama, USA
Title: Inhibition of system Xc- transporter attenuates autoimmune infl ammatory demyelination
Biography
Biography: Tara DeSilva
Abstract
T cell infi ltration into the central nervous system (CNS) is a signifi cant 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 infi ltration in neuroinfl ammatory 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 infl ammatory demyelination. We fi nd that pharmacological and genetic inhibition of system Xc- attenuates chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE). Remarkably, pharmacological blockade of system Xc- seven days aft er induction of EAE attenuated T cell infi ltration 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 infi ltration. We next examined the role of the system Xc- transporter in the CNS aft er immune cell infiltration .Pharmacological inhibitors of the system Xc- transporter administered during the fi rst relapse in a SJL animal model of relapsing-remitting EAE abrogated clinical disease, infl ammation, and myelin loss. Primary co-culture studies demonstrate that myelin-specifi c CD4+ T helper type 1 (Th 1) cells provoke microglia to release glutamate via the system Xc- transporter causing excitotoxic death to mature myelin-producing OLs. Taken together these studies support a novel role for the system Xc- transporter in mediating T cell infi ltration into the CNS as well as promoting myelin destruction aft er immune cell infi ltration in EAE.