Qki is an essential regulator of microglial phagocytosis in demyelination.
Qki is an essential regulator of microglial phagocytosis in demyelination.
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DOI：
10.1084/jem.20190348
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发表时间：
2021-01-04
期刊：
影响因子：
--
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Ren J;Dai C;Zhou X;Barnes JA;Chen X;Wang Y;Yuan L;Shingu T;Heimberger AB;Chen Y;Hu J
小胶质细胞是脑中主要的吞噬细胞类型，然而，小胶质细胞中吞噬调节的潜在机制尚不清楚。Ren等人发现，小胶质细胞中的Qki在很大程度上由脱髓鞘诱导，并且Qki是小胶质细胞中吞噬活性的重要调节剂。在脱髓鞘疾病中调节小胶质细胞吞噬作用的机制尚不清楚。在这里，我们发现小胶质细胞中的Quaking蛋白（Qki）在小鼠和人类大脑中的脱髓鞘中都受到了极大的诱导。小胶质细胞中Quaking基因（Qk）的缺失严重损害了髓鞘碎片的清除。转录组学分析表明，Qki的耗尽损害了总RNA水平和参与吞噬体形成和成熟的基因的剪接。RNA免疫沉淀（RIP）证实了Qki蛋白和参与吞噬作用的Qki靶标的mRNA之间的物理相互作用，表明Qki调节它们的RNA稳定性。Qki耗尽和Qki靶Cd36的抑制都大大降低了小胶质细胞和巨噬细胞的吞噬活性。在小胶质细胞中由Qki耗尽引起的髓鞘碎片的有缺陷的摄取和降解导致未解决的髓鞘碎片，其损害轴突完整性、少突胶质细胞成熟和随后的髓鞘再生。因此，我们的研究结果表明，Qki是一个必不可少的调节小胶质细胞的吞噬活性脱髓鞘条件下。
Microglia is a major phagocytic cell type in the brain; however, the underlying mechanism of phagocytosis regulation in microglia is unclear. Ren et al. discovered that Qki in microglia is greatly induced by demyelination and that Qki is an essential regulator of phagocytic activity in microglia. The mechanism underpinning the regulation of microglial phagocytosis in demyelinating diseases is unclear. Here, we showed that the Quaking protein (Qki) in microglia was greatly induced by demyelination in the brains of both mice and humans. Deletion of the Quaking gene (Qk) in microglia severely impaired the clearance of myelin debris. Transcriptomic profiling indicated that depletion of Qki impaired total RNA levels and splicing of the genes involved in phagosome formation and maturation. RNA immunoprecipitation (RIP) confirmed the physical interactions between the Qki protein and the mRNAs of Qki targets that are involved in phagocytosis, indicating that Qki regulates their RNA stability. Both Qki depletion and inhibition of Qki target Cd36 greatly reduced the phagocytic activity of microglia and macrophages. The defective uptake and degradation of myelin debris caused by Qki depletion in microglia resulted in unresolved myelin debris that impaired axon integrity, oligodendrocyte maturation, and subsequent remyelination. Thus, our results demonstrate that Qki is an essential regulator of microglia’s phagocytic activity under demyelinating conditions.
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