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 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.