Silencing miR-21-5p in sensory neurons reverses neuropathic allodynia via activation of TGF-β-related pathway in macrophages

J Clin Invest. 2023 Jun 1;133(11):e164472. doi: 10.1172/JCI164472.

Abstract

Neuropathic pain remains poorly managed by current therapies, highlighting the need to improve our knowledge of chronic pain mechanisms. In neuropathic pain models, dorsal root ganglia (DRG) nociceptive neurons transfer miR-21 packaged in extracellular vesicles to macrophages that promote a proinflammatory phenotype and contribute to allodynia. Here we show that miR-21 conditional deletion in DRG neurons was coupled with lack of upregulation of chemokine CCL2 after nerve injury and reduced accumulation of CCR2-expressing macrophages, which showed TGF-β-related pathway activation and acquired an M2-like antinociceptive phenotype. Indeed, neuropathic allodynia was attenuated after conditional knockout of miR-21 and restored by TGF-βR inhibitor (SB431542) administration. Since TGF-βR2 and TGF-β1 are known miR-21 targets, we suggest that miR-21 transfer from injured neurons to macrophages maintains a proinflammatory phenotype via suppression of such an antiinflammatory pathway. These data support miR-21 inhibition as a possible approach to maintain polarization of DRG macrophages at an M2-like state and attenuate neuropathic pain.

Keywords: Cellular immune response; Immunology; Macrophages; Neuroscience; Pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ganglia, Spinal / metabolism
  • Humans
  • Hyperalgesia / genetics
  • Hyperalgesia / metabolism
  • Macrophages / metabolism
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Neuralgia* / genetics
  • Neuralgia* / metabolism
  • Neuralgia* / therapy
  • Sensory Receptor Cells / metabolism
  • Transforming Growth Factor beta / metabolism

Substances

  • Transforming Growth Factor beta
  • MicroRNAs
  • MIRN21 microRNA, human