A translational study: Involvement of miR-21-5p in development and maintenance of neuropathic pain via immune-related targets CCL5 and YWHAE

Neuropathic pain occurs in more than half of the patients suffering from peripheral neuropathies. We investigated the role of microRNA (miR)-21 in neuropathic pain using a murine-human translational approach. We applied the spared nerve injury (SNI) model at the sciatic nerve of mice and assessed the potential analgesic effect of perineurial miR-21-5p inhibitor application. Immune-related targets of miR-21-5p were determined by a qRT-PCR based cytokine and chemokine array. Bioinformatical analysis identified potential miR-21-5p targets interacting with CC-chemokine ligand (CCL)5. We validated CCL5 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHAE), an interaction partner of miR-21-5p and CCL5, by qRT-PCR in murine common peroneal and tibial nerves. Validated candidates were then investigated in white blood cell and sural nerve biopsy samples of patients with focal to generalized pain syndromes, i.e. small fiber neuropathy (SFN), polyneuropathy (PNP), and nerve lesion (NL). We showed that perineurial miR-21-5p inhibition reverses SNI-induced mechanical and heat hypersensitivity in mice and found a reduction of the SNI-induced increase of the pro-inflammatory mediators CCL5 (p