T cell infiltration into the central nervous system (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− seven days 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 co-culture studies
demonstrate that myelin-specific CD4+ T helper type 1 (Th1) 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 infiltration into the CNS as well as promoting myelin destruction after
immune cell infiltration in EAE.
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