Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome
Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome
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DOI：
10.1523/jneurosci.0993-19.2019
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发表时间：
2020-02-12
影响因子：
5.3
通讯作者：
Sierra, Amanda
中科院分区：
文献类型：
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作者：
Diaz-Aparicio, Irune;Paris, Inaki;Sierra, Amanda
在成年海马神经发生过程中，大多数新生细胞会发生凋亡，并被驻留的小胶质细胞迅速吞噬，以防止细胞内内容物的溢出。在这里，我们认为吞噬作用不仅是被动的身体清除，而且在维持神经发生方面具有积极的作用。首先，我们发现在长期缺乏两条吞噬途径的雄性和雌性小鼠中，神经发生被破坏：嘌呤能受体P2Y12和家族Mer酪氨酸激酶(MerTK/Ax1)的酪氨酸激酶。相反，在MerTK表达有条件下调的小鼠中，神经发生一过性增加。接下来，我们对体外培养的小胶质细胞吞噬引起的变化进行了转录转录分析，并确定了与代谢、染色质重塑和神经发生相关功能相关的基因。最后，我们发现吞噬小胶质细胞的分泌体在体内和体外都限制了新神经元的产生。我们的数据表明，小胶质细胞作为局部细胞死亡的感受器，通过吞噬分泌体调节神经源性缝隙中的增殖和生存之间的平衡，从而支持成年海马神经发生的长期维持。
During adult hippocampal neurogenesis, most newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of intracellular contents. Here, we propose that phagocytosis is not merely passive corpse removal but has an active role in maintaining neurogenesis. First, we found that neurogenesis was disrupted in male and female mice chronically deficient for two phagocytosis pathways: the purinergic receptor P2Y12, and the tyrosine kinases of the TAM family Mer tyrosine kinase (MerTK)/Axl. In contrast, neurogenesis was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of the changes induced by phagocytosis in microglia in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro. Our data suggest that microglia act as a sensor of local cell death, modulating the balance between proliferation and survival in the neurogenic niche through the phagocytosis secretome, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.