CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model.
CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model.
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DOI：
10.1016/j.molimm.2010.08.007
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发表时间：
2010-11
影响因子：
3.6
通讯作者：
Martin BK
中科院分区：
文献类型：
--
作者：
Ingersoll SA;Martin CB;Barnum SR;Martin BK
已知中枢神经系统（CNS）中的脱髓鞘涉及几种免疫效应机制，包括补体蛋白。脑中胶质细胞局部产生的补体既有害又有保护作用。为了研究C3 a和C5 a在脱髓鞘和髓鞘再生病理学中的作用，我们利用铜腙模型。与野生型小鼠相比，在胶质细胞酸性蛋白（GFAP）启动子控制下表达C3 a或C5 a的转基因小鼠的胼胝体脱髓鞘和髓鞘再生轻微延迟。C3 a和C5 a转基因小鼠由于小胶质细胞的活化和/或迁移增加，胼胝体中的细胞结构增加。在C3 a和C5 a转基因小鼠的早期髓鞘再生事件期间，少突胶质细胞以更高的数量迁移到胼胝体，从而使这些小鼠在10周研究结束时能够与WT小鼠一样有效地进行髓鞘再生。为了确定C3 a和/或C5 a对单个神经胶质细胞亚群的影响，我们创建了鼠重组C3 a和C5 a蛋白。当用C3 a和/或C5 a刺激小胶质细胞和混合胶质细胞培养物时，我们观察到促炎细胞因子和趋化因子的产生增加。相反，星形胶质细胞在C3 a和/或C5 a存在下细胞因子和趋化因子的产生减少。我们还发现，MAPK通路蛋白JNK和ERK 1/2在神经胶质细胞被激活后，刺激C3 a和C5 a。总的来说，我们的研究结果表明，尽管大脑中C3 a和C5 a的产生在脱髓鞘过程中起着负面作用，但这些蛋白质可能有助于髓鞘再生。
Demyelination in the central nervous system (CNS) is known to involve several immune effector mechanisms, including complement proteins. Local production of complement by glial cells in the brain can be both harmful and protective. To investigate the roles of C3a and C5a in demyelination and remyelination pathology we utilized the cuprizone model. Transgenic mice expressing C3a or C5a under the control of the glial fibrillary acidic protein (GFAP) promoter had exacerbated demyelination and slightly delayed remyelination in the corpus callosum compared to WT mice. C3a and C5a transgenic mice had increased cellularity in the corpus callosum due to increase activation and/or migration of microglia. Oligodendrocytes migrated to the corpus callosum in higher numbers during early remyelination events in C3a and C5a transgenic mice, thus enabling these mice to remyelinate as effectively as WT mice by the end of the 10 week study. To determine the effects of C3a and/or C5a on individual glial subsets, we created murine recombinant C3a and C5a proteins. When microglia and mixed glial cultures were stimulated with C3a and/or C5a, we observed an increase in the production of proinflammatory cytokines and chemokines. In contrast, astrocytes had decreased cytokine and chemokine production in the presence of C3a and/or C5a. We also found that the MAPK pathway proteins JNK and ERK1/2 were activated in glia upon stimulation with C3a and C5a. Overall, our findings show that although C3a and C5a production in the brain play a negative role during demyelination, these proteins may aid in remyelination.
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