Reduced Immunoproteasome Formation and Accumulation of Immunoproteasomal Precursors in the Brains of Lymphocytic Choriomeningitis Virus-Infected Mice
Reduced Immunoproteasome Formation and Accumulation of Immunoproteasomal Precursors in the Brains of Lymphocytic Choriomeningitis Virus-Infected Mice
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DOI：
10.4049/jimmunol.1001517
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发表时间：
2010-11-01
影响因子：
4.4
通讯作者：
Groettrup, Marcus
中科院分区：
文献类型：
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作者：
Kremer, Marcel;Henn, Anja;Groettrup, Marcus
组织炎症伴随着免疫蛋白酶体对组成性蛋白酶体的精氨酸介导的替换，其最终导致用于Ag呈递的MHC I类限制性表位的优化生成。大脑被认为是一个免疫豁免的器官，其中特殊的解剖结构以及主动耐受机制抑制炎症反应的发展，并有助于防止免疫病理损伤。我们分析了免疫蛋白酶体表达的淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染后，在大脑中，可以表明，LCMV感染的小鼠导致诱导蛋白酶体亚基在大脑中的转录诱导。然而，与其他器官相比，腹腔内甚至颅内感染LCMV仅导致脑中成熟免疫蛋白酶体的微弱表达，并导致免疫蛋白酶体前体的积聚。通过免疫组织学，我们可以确定小胶质细胞样细胞作为免疫蛋白酶体的主要生产者，而在星形胶质细胞免疫蛋白酶体的表达几乎只限于细胞核。免疫蛋白酶体亚单位低分子量多肽2，也不多催化内肽酶复合物样1在神经元或少突胶质细胞中检测。IFN-γ刺激的原代星形胶质细胞的体外研究表明，所观察到的免疫蛋白酶体前体复合物的积累发生在该细胞群中。在功能上，免疫蛋白酶体的缺乏延长了LMP 7（-/-）小鼠中LCMV诱导的脑膜炎的严重程度并降低了其严重程度，这表明小胶质细胞中的免疫蛋白酶体有助于加剧免疫病理损伤。我们假设一个postpersonally调节机制，防止丰富的和不适当的免疫蛋白酶体组装在大脑中，并可能有助于保护再生不良的中枢神经系统细胞免疫病理破坏。免疫学杂志，2010，185：5549-5560。
Tissue inflammation is accompanied by the cytokine-mediated replacement of constitutive proteasomes by immunoproteasomes that finally leads to an optimized generation of MHC class I restricted epitopes for Ag presentation. The brain is considered an immunoprivileged organ, where both the special anatomy as well as active tolerance mechanisms repress the development of inflammatory responses and help to prevent immunopathological damage. We analyzed the immunoproteasome expression in the brain after an infection with lymphocytic choriomeningitis virus (LCMV) and could show that LCMV-infection of mice leads to the transcriptional induction of inducible proteasome subunits in the brain. However, compared with other organs, i.p. and even intracranial infection with LCMV only led to a faint expression of mature immunoproteasome in the brain and resulted in the accumulation of immunoproteasomal precursors. By immunohistology, we could identify microglia-like cells as the main producers of immunoproteasome, whereas in astrocytes immunoproteasome expression was almost exclusively restricted to nuclei. Neither the immunoproteasome subunits low molecular mass polypeptide 2 nor multicatalytic endopeptidase complex-like-1 were detected in neurons or oligodendrocytes. In vitro studies of IFN-gamma-stimulated primary astrocytes suggested that the observed accumulation of immunoproteasomal precursor complexes takes place in this cell population. Functionally, the lack of immunoproteasomes protracted and lowered the severity of LCMV-induced meningitis in LMP7(-/-) mice suggesting a contribution of immunoproteasomes in microglia to exacerbate immunopathological damage. We postulate a posttranslationally regulated mechanism that prevents abundant and inappropriate immunoproteasome assembly in the brain and may contribute to the protection of poorly regenerating cells of the CNS from immunopathological destruction. The Journal of Immunology, 2010, 185: 5549-5560.