Inhibition of System Xc− Transporter Attenuates Autoimmune Inflammatory Demyelination

Abstract

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.

Fluorescence-based measurement of cystine uptake through xCT shows requirement for ROS detoxification in activated lymphocytes

“…The in vivo relevance of cystine uptake for T cell function was studied by Evonuk et al (Evonuk et al, 2015). These studies demonstrated that autoreactive T cells in experimental autoimmune encephalomyelitis (EAE) require cystine uptake for their function as pharmacological blockade or genetic deletion of xCT prevented EAE.…”

“…Cystine uptake is required for T cell activation (Srivastava et al, 2010) and activated T cells require extracellular cystine for proliferation (Levring et al, 2012) and DNA synthesis (Levring et al, 2015). Autoreactive T cells depend on cystine uptake as pharmacologic blockade attenuates experimental autoimmune encephalomyelitis (EAE) and Slc7a11-deficient mice are protected from EAE (Evonuk et al, 2015). Interestingly, myeloid derived suppressor cells (MDSC) are proposed to block T cells in part by depleting extracellular cystine that impairs anti -tumor T cell response (Srivastava et al, 2010).…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Similar to astrocytes, increases in inflammatory cytokines such as TNF and IL-1β are known to impair glutamate buffering and clearance by oligodendrocyte EAATs, and trigger glutamate toxicity (Takahashi et al, 2003a;Takahashi et al, 2003b). Indeed, inhibition of the expression and functioning of glutamate transporters such as EAATs and xC-transporters in axonal tracts is sufficient to induce oligodendrocyte loss and demyelination, which undermines brain connectivity (Domercq et al, 2007;Evonuk et al, 2015).…”

Absence of system xc − on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

“…In C3H/HeSnJSlc7a11 sut/sut (sut/sut) mice that are deficient for system x c − , proteolipid protein (PLP)-induced EAE was attenuated compared to their wild type littermates. The latter effect could be replicated by pharmacological inhibition of system x c − with sulfasalazine (SAS) and (S)-4-carboxyphenylglycine [43]. Whereas the above-described studies suggest that enhancement of system x c − contributes to the pathogenesis of MS, a recent report of Morales Pantoja et al showed diminished xCT mRNA and protein levels in the mouse spinal cord during the course of myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide-induced EAE [44].…”