Interleukin-1beta impedes oligodendrocyte progenitor cell recruitment and white matter repair following chronic cerebral hypoperfusion.
Interleukin-1beta impedes oligodendrocyte progenitor cell recruitment and white matter repair following chronic cerebral hypoperfusion.
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Interleukin-1beta 会阻碍慢性脑灌注不足后少突胶质细胞祖细胞的募集和白质修复。
DOI：
10.1016/j.bbi.2016.09.024
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Hu Weiwei
中科院分区：
文献类型：
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作者：
Zhou Yiting;Zhang Jing;Wang Lu;Chen Ying;Wan Yushan;He Yang;Jiang Lei;Ma Jing;Liao Rujia;Zhang Xiangnan;Shi Liyun;Qin Zhenghong;Zhou Yudong;Chen Zhong;Hu Weiwei
皮质下缺血性血管性痴呆（SIVD）由慢性脑灌注不足引起，表现为进行性白色物质和认知功能障碍。然而，其发病机制知之甚少。本研究探讨了白细胞介素1β（IL-1β）及其受体IL-1受体1（IL-1 R1）在小鼠单侧颈总动脉阻断（rUCCAO）所致SIVD模型中的作用。我们发现rUCCAO后早期胼胝体中IL-1β表达升高。在rUCCAO后早期给予IL-1受体拮抗剂（IL-1 Ra）以及IL-1 R1敲除可挽救髓鞘碱性蛋白（MBP）的下调，并改善后期的髓鞘再生。我们的数据表明，OPCs的募集，而不是OPCs的增殖或分化，是慢性脑缺血后髓鞘再生的唯一受损步骤。IL-1 Ra治疗和IL-1 R1敲除对少突胶质祖细胞（OPC）增殖没有影响，但促进了新生成的OPC向胼胝体的募集，这可以通过IL-1 R1敲除小鼠SVZ中IL-1 R1的代偿性表达来逆转。此外，我们发现募集的OPCs有助于少突胶质细胞的再生和功能恢复。在transwell试验中，IL-1β通过IL-1 R1抑制OPC迁移。此外，KdPT可以进入大脑阻断IL-1 R1也显示出相当的保护时，腹腔内交付。我们的研究结果表明，在慢性脑灌注不足后的早期阶段，IL-1β通过IL-1 R1阻碍OPC募集，从而抑制白色修复和功能恢复。IL-1 R1抑制剂可能在SIVD的治疗中具有潜在的用途。
Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion exhibits progressive white matter and cognitive impairments. However, its pathogenetic mechanisms are poorly understood. We investigated the role of interleukin-1β (IL-1β) and its receptor IL-1 receptor type 1 (IL-1R1) in an experimental SIVD model generated via right unilateral common carotid arteries occlusion (rUCCAO) in mice. We found that IL-1β expression was elevated in the corpus callosum at the early stages after rUCCAO. IL-1 receptor antagonist (IL-1Ra), when delivered at an early stage, as well asIL-1R1knockout, rescued the downregulation of myelin basic protein (MBP) and improved remyelination at the later stage after rUCCAO. Our data suggest that the recruitment of OPCs, but not the proliferation or differentiation of OPCs, is the only compromised step of remyelination following chronic cerebral ischemia. IL-1Ra treatment andIL-1R1knockout had no effect on the oligodendrocyte progenitor cell (OPC) proliferation, but did promote the recruitment of newly generated OPCs to the corpus callosum, which can be reversed by compensatory expression of IL-1R1 in the SVZ ofIL-1R1knockout mice. Further, we found that recruited OPCs contribute to oligodendrocyte regeneration and functional recovery. In transwell assays, IL-1β inhibited OPC migration through IL-1R1. Moreover, KdPT which can enter the brain to block IL-1R1 also showed comparable protection when intraperitoneally delivered. Our results suggest that IL-1β during the early stages following chronic cerebral hypoperfusion impedes OPC recruitment via IL-1R1, which inhibits white matter repair and functional recovery. IL-1R1 inhibitors may have potential uses in the treatment of SIVD.