Ceria nanoparticles ameliorate white matter injury after intracerebral hemorrhage: microglia-astrocyte involvement in remyelination.
Ceria nanoparticles ameliorate white matter injury after intracerebral hemorrhage: microglia-astrocyte involvement in remyelination.
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二氧化铈纳米粒子改善脑出血后白质损伤：小胶质细胞-星形胶质细胞参与髓鞘再生
DOI：
10.1186/s12974-021-02101-6
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发表时间：
2021-02-15
影响因子：
9.3
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zheng J;Lu J;Mei S;Wu H;Sun Z;Fang Y;Xu S;Wang X;Shi L;Xu W;Chen S;Yu J;Liang F;Zhang J
脑出血（ICH）可诱导活性氧（ROS）的过度积累，从而导致严重的白质损伤。少突胶质细胞祖细胞（OPC）的分化过程是由小胶质细胞和星形胶质细胞协调的，ROS也驱动小胶质细胞和星形胶质细胞的激活。鉴于氧化铈纳米颗粒（CeNP）具有强大的活性氧清除能力，我们旨在研究用CeNP治疗是否通过调节活性氧诱导的小胶质细胞极化和星形胶质细胞改变来改善白质损伤。方法采用胶原酶7在体内诱导脑出血。小鼠被给予PLX3397以消耗小胶质细胞。体外实验采用原代小胶质细胞和星形胶质细胞。透射电镜分析和免疫染色证实了CeNP在髓鞘再生和OPC分化中的积极作用。流式细胞术、实时聚合酶链反应、免疫荧光和western blotting检测小胶质细胞极化、星形胶质细胞改变及其分子机制。结果scenp对ros诱导的小胶质细胞和星形胶质细胞NF-κB p65易位均有较强的抑制作用，并显著降低M1小胶质细胞和A1星形胶质细胞的表达。此外，我们发现，CeNP治疗促进脑出血后的髓鞘再生和OPC分化，而这种作用在小胶质细胞耗尽后得到缓解。有趣的是，我们还发现，与ICH +对照剂+ PLX3397组相比，ICH + CeNP + PLX3397处理的小鼠成熟少突胶质细胞数量适度增加。因此，星形胶质细胞可能参与了这一病理生理过程。随后的吞噬实验表明，A1星形胶质细胞高表达C3， C3可以与小胶质细胞C3aR结合，阻碍小胶质细胞吞噬髓磷脂碎片。这一结果进一步补充了星形胶质细胞到小胶质细胞的反馈机制。结论本研究揭示了脑出血后脑白质损伤的新机制：脑出血通过ros诱导的NF-κB p65易位诱导M1小胶质细胞和A1星形胶质细胞，阻碍OPC成熟。随后，A1星形胶质细胞通过星形胶质细胞c3 -小胶质细胞C3aR轴抑制小胶质细胞吞噬髓磷脂碎片。聚乙二醇- cenp处理可抑制这一病理过程，并最终促进髓鞘再生。这些发现提示我们在今后的工作中应将星形胶质细胞和小胶质细胞作为一个功能单位。
BackgroundIntracerebral hemorrhage (ICH) can induce excessive accumulation of reactive oxygen species (ROS) that may subsequently cause severe white matter injury. The process of oligodendrocyte progenitor cell (OPC) differentiation is orchestrated by microglia and astrocytes, and ROS also drives the activation of microglia and astrocytes. In light of the potent ROS scavenging capacity of ceria nanoparticles (CeNP), we aimed to investigate whether treatment with CeNP ameliorates white matter injury by modulating ROS-induced microglial polarization and astrocyte alteration.MethodsICH was induced in vivo by collagenase VII injection. Mice were administered with PLX3397 for depleting microglia. Primary microglia and astrocytes were used for in vitro experiments. Transmission electron microscopy analysis and immunostaining were performed to verify the positive effects of CeNP in remyelination and OPC differentiation. Flow cytometry, real-time polymerase chain reaction, immunofluorescence and western blotting were used to detect microglia polarization, astrocyte alteration, and the underlying molecular mechanisms.ResultsCeNP treatment strongly inhibited ROS-induced NF-κB p65 translocation in both microglia and astrocytes, and significantly decreased the expression of M1 microglia and A1 astrocyte. Furthermore, we found that CeNP treatment promoted remyelination and OPC differentiation after ICH, and such effects were alleviated after microglial depletion. Interestingly, we also found that the number of mature oligodendrocytes was moderately increased in ICH + CeNP + PLX3397-treated mice compared to the ICH + vehicle + PLX3397 group. Therefore, astrocytes might participate in the pathophysiological process. The subsequent phagocytosis assay indicated that A1 astrocyte highly expressed C3, which could bind with microglia C3aR and hinder microglial engulfment of myelin debris. This result further replenished the feedback mechanism from astrocytes to microglia.ConclusionThe present study reveals a new mechanism in white matter injury after ICH: ICH induces M1 microglia and A1 astrocyte through ROS-induced NF-κB p65 translocation that hinders OPC maturation. Subsequently, A1 astrocytes inhibit microglial phagocytosis of myelin debris via an astrocytic C3-microglial C3aR axis. Polyethylene glycol-CeNP treatment inhibits this pathological process and ultimately promotes remyelination. Such findings enlighten us that astrocytes and microglia should be regarded as a functional unit in future works.
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影响因子：
7.4
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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