Enhanced Integrated Stress Response Promotes Myelinating Oligodendrocyte Survival in Response to Interferon-γ
Enhanced Integrated Stress Response Promotes Myelinating Oligodendrocyte Survival in Response to Interferon-γ
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DOI：
10.2353/ajpath.2008.080449
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发表时间：
2008-11-01
影响因子：
6
通讯作者：
Popko, Brian
中科院分区：
文献类型：
--
作者：
Lin, Wensheng;Kunkler, Phillip E.;Popko, Brian
T细胞来源的多效性细胞因子干扰素-γ被认为在免疫介导的中枢神经系统脱髓鞘疾病中发挥关键调节作用，包括多发性硬化症和实验性自身免疫性脑脊髓炎。我们以前的工作已经证明，内质网(ER)应激反应调节少突胶质细胞对该细胞因子的反应。内质网应激反应激活胰腺ER激酶，它通过磷酸化翻译起始因子2α(eIF2α)来协调其整合的应激反应的适应程序。在这项研究中，我们发现生长停滞和DNA损伤34(Gadd34)，一个压力诱导的磷酸酶复合体的调节亚基，可以去磷酸化eIF2α，在中枢神经系统异位表达干扰素-γ的小鼠髓鞘形成的少突胶质细胞中选择性地上调。我们还发现，Gadd34突变株小鼠在接触干扰素-γ时，髓鞘少突胶质细胞中磷酸化eIF2α(p-eIF2α)水平增加，少突胶质细胞丢失和髓鞘减少。此外，用salubrine(一种专门抑制蛋白磷酸酶1(PP1)-Gadd34磷酸酶活性的小化合物)处理后，p-eIEF2α的水平增加，并改善了暴露于干扰素-γ的培养海马片的髓鞘减少和少突胶质细胞丢失。因此，我们的数据提供了证据表明，增强的综合应激反应可以促进免疫介导的脱髓鞘疾病中少突胶质细胞的存活。(Am J Pathol2008173：15081517；DOI：10.2353/ajpath.2008.080449)
The T-cell-derived, pleiotropic cytokine interferon (IFN)-gamma is believed to play a key regulatory role in immune-mediated demyelinating disorders of the central nervous system, including multiple sclerosis and experimental autoimmune encephalomyelitis. Our previous work has demonstrated that the endoplasmic reticulum (ER) stress response modulates the response of oligodendrocytes to this cytokine. The ER stress response activates the pancreatic ER kinase, which coordinates an adaptive program known its the integrated stress response by phosphorylating translation initiation factor 2 alpha (eIF2 alpha). In this study, we found that growth arrest and DNA damage 34 (GADD34), a stress-inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2 alpha, was selectively up-regulated in Myelinating oligodendrocytes in mice that ectopically expressed IFN-gamma in the central nervous system. We also found that it GADD34 mutant strain of mice displayed increased levels of phosphorylated eIF2 alpha (p-eIF2 alpha) in myelinating oligodendrocytes when exposure to IFN-gamma, as well as diminished oligodendrocyte loss and hypomyelination. Furthermore, treatment with salubrinal, a small chemical compound that specifically inhibits protein phosphatase 1(PP1)-GADD34 phosphatase activity, increased the levels of p-eIEF2 alpha and ameliorated hypomyelination and oligodendrocyte loss in cultured hippocampal slices exposed to IFN-gamma. Thus, our data provide evidence that an enhanced integrated stress response could promote oligodendrocyte survival in immune-mediated demyelination diseases. (Am J Pathol 2008, 173:1508-1517; DOI: 10.2353/ajpath.2008.080449)