smallRNA-sequencing reveals microRNAs as endogenous Toll-like receptor ligands causing neuroinflammation

To identify microRNAs as TLR-activating molecules we have induced apoptosis in primary cortical neurons to trigger specific microRNA release into media. smallRNA sequencing revealed potential microRNAs ligands derived from dying neurons and their corresponding media that harbor already described TLR7/8 activating sequences. In line with this finding, about 80% of our differentially present miRNAs were able to activate TLR7/8 reporter cell lines. Furthermore, microRNAs miR-340-3p and miR-132-5p induced a specific cytokine and chemokine release form microglia leading to neuronal death. Within our systematic approach, we have identified TLR paralog-specific activating microRNAs with the potential to serve as biomarkers for brain diseases. Apoptotic neurons release microRNAs as endogenous signaling molecules extracellular that are endosmal TLR7 and TLR8 ligands.