MiR-451 Elevation Relieves Inflammatory Pain by Suppressing Microglial Activation-evoked Inflammatory Response Via Targeting TLR4

Microglia-mediated neuroinflammation in spinal cord fulfills the pivotal role in the pathogenesis of chronic inflammatory pain. Emerging evidence confirms the anti-inflammatory effects of microRNA (miR)-451 in several inflammation-related diseases. Nevertheless, its function in the development of inflammatory pain is still poorly defined. In this study, the expression of miR-451 was decreased in spinal dorsal horn and spinal microglia of complete Freund's adjuvant (CFA)-induced inflammatory pain mice model. In vitro, the ectopic expression of miR-451 inhibited LPS-triggered microglial activation by reducing NO production and microglia marker IBA-1 expression. Notably, miR-451 overexpression antagonized microglial activation-induced pro-inflammatory cytokine transcripts and releases, including IL-6, IL-1β, and TNF-α. Mechanism analysis corroborated that miR-451 elevation abrogated LPS-induced expression of TLR4, which was identified as a direct target of miR-451 by bioinformatics and a dual-firefly luciferase reporter assay. Intriguingly, overexpression of miR-451 counteracted the inhibitory effects of miR-451 on microglia inflammation. Additionally, restoring miR-451 expression in vivo alleviated CFA-evoked mechanical allodynia and thermal hyperalgesia in an inflammatory pain model. Concomitantly, administration of miR-451 lentiviral particles also attenuated CFA-induced inflammatory response and microglia activation, concomitant with a reduction in TLR4 expression in spinal cord. Collectively, the current research suggests that miR-451 may relieve chronic inflammatory pain by inhibiting microglia activation-mediated inflammation via targeting TLR4, supporting a promising approach for inflammatory pain therapy.