Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Exp Neurol. 2015 Jul;269:202-12. doi: 10.1016/j.expneurol.2015.04.011. Epub 2015 Apr 24.
Inflammatory responses are known to play critical roles in the regulation of neurodevelopment and neurodegeneration. Although microglial cells are recognized as professional immune cells in brains, recent evidence suggests that neurons also express important receptors and regulators of innate immunity, including Toll-like receptor 7 (TLR7), which is a receptor for single-stranded RNAs (ssRNAs). Here, we report that neuronal TLR7 recognizes endogenous ligands such as the miRNAs Let7c and miR21 and plays a negative role in controlling neuronal growth in a cell-autonomous manner. We show here that hippocampal CA1 neurons in Tlr7(-/Y) mice had more complex dendritic arbors compared with those of wild-type littermates at postnatal (P) day 7, but not at P21. This observation strengthens a role of TLR7 in restricting neuronal growth during development. In cultured neurons, transient knockdown of Tlr7 promoted axonal and dendritic growth, supporting the cell-autonomous effect of TLR7 on neuronal growth. We observed perceptible levels of Let7c and miR21 in the exosomes of the neuronal cultures as well as in developing brains. Treatment with Let7c and miR21 restricted dendritic growth of wild-type neurons but not Tlr7(-/-) neurons. Our study suggests that neuronal TLR7 is activated by endogenous ligands and thus regulates neuronal morphology. Neuronal innate immune responses may influence neurodevelopment and neurodegeneration through the regulation of neuronal morphology.
炎症反应被认为在神经发育和神经退行性变的调节中起着关键作用。虽然小胶质细胞被认为是大脑中的专业免疫细胞，但最近的证据表明，神经元也表达重要的先天免疫受体和调节剂，包括 Toll 样受体 7（TLR7），它是单链 RNA（ssRNA）的受体。在这里，我们报告神经元 TLR7 识别内源性配体，如 Let7c 和 miR21，并以细胞自主的方式发挥负调控神经元生长的作用。我们在这里显示，Tlr7(-/Y) 小鼠的海马 CA1 神经元在出生后第 7 天（P7）与野生型同窝仔相比，具有更复杂的树突分支，但在 P21 时则没有。这一观察结果加强了 TLR7 在发育过程中限制神经元生长的作用。在培养的神经元中，TLR7 的瞬时敲低促进了轴突和树突的生长，支持 TLR7 对神经元生长的细胞自主作用。我们在神经元培养物的外泌体以及发育中的大脑中观察到明显水平的 Let7c 和 miR21。Let7c 和 miR21 的处理限制了野生型神经元的树突生长，但不限制 Tlr7(-/-)神经元的生长。我们的研究表明，神经元 TLR7 被内源性配体激活，从而调节神经元形态。神经元先天免疫反应可能通过调节神经元形态影响神经发育和神经退行性变。
