Context dependent role of miR-486 promoting neuroregeneration of primary sensory neurons downstream of interleukin-6 signal transducer

The pro-inflammatory cytokine interleukin-6 (IL-6) via its IL-6 signal transducer (IL6ST/gp130) plays an important role in neuronal survival, neuro-regeneration, and pathological pain. While its critical importance in the nervous system is well established, the underlying molecular mechanisms and the involvement of microRNAs (miRNAs) as critical regulators of biological processes in health and disease are not sufficiently understood. We identified miR-486-5p as the single significantly deregulated miRNA in sensory neurons with a conditional depletion of gp130. In situ hybridization and immunofluorescence in dorsal root ganglia (DRG) localized miR-486 to small diameter neurons, including peptidergic nociceptors. miR-486^−/− mice exhibited normal baseline and neuropathic pain-like behaviors and recovered similarly to wild-type (WT) littermate controls in response to sciatic crush injury. On the other hand, DRG neurons derived from mice with a conditional deletion of IL6ST/gp130 in Na_v1.8-expressing primary afferent nociceptors (SNS-gp130^−/−) show strongly compromised neuro-regeneration, which was significantly rescued by overexpressing miR-486, indicative of a specific role of miR-486 in IL-6/gp130-dependent neuro-regenerative processes. Our findings highlight context-dependent differential expression and roles of miRNAs after nerve injury driving nerve regeneration versus neuropathic pain.