Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination.
Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination.
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DOI：
10.4049/jimmunol.1401108
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发表时间：
2015-07-15
期刊：
影响因子：
--
通讯作者：
DeSilva TM
中科院分区：
文献类型：
--
作者：
Evonuk KS;Baker BJ;Doyle RE;Moseley CE;Sestero CM;Johnston BP;De Sarno P;Tang A;Gembitsky I;Hewett SJ;Weaver CT;Raman C;DeSilva TM
T 细胞浸润中枢神经系统 (CNS) 是自身免疫性炎症脱髓鞘疾病的重要潜在发病机制。多项证据表明，中枢神经系统中的谷氨酸失调是神经炎症性脱髓鞘疾病中免疫细胞浸润的重要后果。然而，炎症与谷氨酸失调之间的因果关系尚不清楚。氧化应激过程中谷氨酸释放的主要来源是 xc− 转运蛋白系统，然而，这种机制尚未在自身免疫性炎症脱髓鞘动物模型中进行测试。我们发现 xc− 系统的药理学和遗传抑制可减轻慢性和复发缓解型实验性自身免疫性脑脊髓炎 (EAE)。值得注意的是，诱导 EAE 7 天后对系统 xc− 进行药理学封锁会减弱 T 细胞对 CNS 的浸润，但不会减弱外周 T 细胞的激活。携带 Slc7a11 (xCT) 突变（使 xc− 系统失活）的小鼠对 EAE 具有抵抗力，证实了 xc− 系统在介导免疫细胞浸润中的核心作用。接下来我们检查了免疫细胞浸润后中枢神经系统中 xc− 转运蛋白系统的作用。在复发缓解型 EAE 的 SJL 动物模型中，在首次复发期间施用 xc− 转运蛋白系统的药理学抑制剂，可消除临床疾病、炎症和髓鞘质损失。原代共培养研究表明，髓磷脂特异性 CD4+ T 辅助 1 型 (Th1) 细胞会刺激小胶质细胞通过 xc− 转运蛋白系统释放谷氨酸，导致成熟的产生髓磷脂的 OL 发生兴奋性毒性死亡。总而言之，这些研究支持 xc− 转运蛋白系统在介导 T 细胞浸润中枢神经系统以及在 EAE 中免疫细胞浸润后促进髓磷脂破坏方面发挥新作用。
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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DOI：
10.4049/jimmunol.181.1.338
发表时间：
2008-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
De Sarno P;Axtell RC;Raman C;Roth KA;Alessi DR;Jope RS
通讯作者：
Jope RS
DOI：
10.1523/jneurosci.6129-08.2009
发表时间：
2009-06-17
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
DeSilva TM;Kabakov AY;Goldhoff PE;Volpe JJ;Rosenberg PA
通讯作者：
Rosenberg PA
影响因子：
4.2
作者：
Buntinx, M;Moreels, M;Ameloot, M
通讯作者：
Ameloot, M
影响因子：
2.5
作者：
HEWETT, SJ;CORBETT, JA;CHOI, DW
通讯作者：
CHOI, DW
影响因子：
2.2
作者：
Goebel, Kerstin;Bittner, Stefan;Meuth, Sven G.
通讯作者：
Meuth, Sven G.