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

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.

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Correspondence to Hongxing Zhang.

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For experiments in mice, all protocols were conducted in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals, and approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University Health Science Center, Honghui Hospital.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving animals were performed according to the National Institutes of Health guide for the care and use of Laboratory animals, and approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University Health Science Center, Honghui Hospital.

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Sun, X., Zhang, H. miR-451 elevation relieves inflammatory pain by suppressing microglial activation-evoked inflammatory response via targeting TLR4. Cell Tissue Res 374, 487–495 (2018). https://doi.org/10.1007/s00441-018-2898-7

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Keywords

  • Inflammatory pain
  • mir-451
  • Microglial activation
  • Inflammation
  • TLR4