miR-451 elevation relieves inflammatory pain by suppressing microglial activation-evoked inflammatory response via targeting TLR4

Cell Tissue Res. 2018 Dec;374(3):487-495. doi: 10.1007/s00441-018-2898-7. Epub 2018 Aug 1.

Abstract

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.

Keywords: Inflammation; Inflammatory pain; Microglial activation; TLR4; mir-451.

MeSH terms

  • Animals
  • Base Sequence
  • Disease Models, Animal
  • Freund's Adjuvant
  • Inflammation / genetics*
  • Inflammation / pathology
  • Lipopolysaccharides
  • Male
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Microglia / metabolism
  • Microglia / pathology*
  • Pain / genetics
  • Pain / pathology
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Lipopolysaccharides
  • MicroRNAs
  • Mirn451 microRNA, mouse
  • Toll-Like Receptor 4
  • Freund's Adjuvant