The microRNAs Let7c and miR21 are recognized by neuronal Toll-like receptor 7 to restrict dendritic growth of neurons

• Tlr7 is expressed in neurons.
• TLR7 cell-autonomously downregulates axonal and dendritic growth of neurons.
• Let7b, Let7c and miR21 are expressed in cultured neurons and brains.
• Let7c and miR21 restrict dendritic growth via TLR7 activation.

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.