TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG

Toll-like receptors (TLRs) are nucleic acid–sensing receptors and have been implicated in mediating pain and itch. Here we report that Tlr8–/– mice show normal itch behaviors, but have defects in neuropathic pain induced by spinal nerve ligation (SNL) in mice. SNL increased TLR8 expression in small-diameter IB4+ DRG neurons. Inhibition of TLR8 in the DRG attenuated SNL-induced pain hypersensitivity. Conversely, intrathecal or intradermal injection of TLR8 agonist, VTX-2337, induced TLR8-dependent pain hypersensitivity. Mechanistically, TLR8, localizing in the endosomes and lysosomes, mediated ERK activation, inflammatory mediators’ production, and neuronal hyperexcitability after SNL. Notably, miR-21 was increased in DRG neurons after SNL. Intrathecal injection of miR-21 showed the similar effects as VTX-2337 and inhibition of miR-21 in the DRG attenuated neuropathic pain. The present study reveals a previously unknown role of TLR8 in the maintenance of neuropathic pain, suggesting that miR-21–TLR8 signaling may be potential new targets for drug development against this type of chronic pain.

Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Zhang, Z.-J., Guo, J.-S., Li, S.-S., Wu, X.-B., Cao, D.-L., Jiang, B.-C., Jing, P.-B., Bai, X.-Q., Li, C.-H., Wu, Z.-H., Lu, Y., Gao, Y.-J. Tags: Neuroinflammation, Neuroscience Articles Source Type: research