Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice

J Neuroinflammation. 2016 Jul 11;13(1):183. doi: 10.1186/s12974-016-0652-1.


Background: Trigeminal nerve damage-induced neuropathic pain is a severely debilitating chronic orofacial pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of spinal nerve ligation-induced neuropathic pain. Whether and how CXCL13/CXCR5 in the trigeminal ganglion (TG) mediates orofacial pain are unknown.

Methods: The partial infraorbital nerve ligation (pIONL) was used to induce trigeminal neuropathic pain in mice. The expression of ATF3, CXCL13, CXCR5, and phosphorylated extracellular signal-regulated kinase (pERK) in the TG was detected by immunofluorescence staining and western blot. The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing.

Results: pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG. Inhibition of CXCL13 or CXCR5 by shRNA lentivirus attenuated pIONL-induced mechanical allodynia. Additionally, pIONL-induced neuropathic pain and the activation of ERK in the TG were reduced in Cxcr5 (-/-) mice. Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL. TNF-α inhibitor (Etanercept) and IL-1β inhibitor (Diacerein) attenuated pIONL-induced orofacial pain. Finally, intra-TG injection of CXCL13 induced mechanical allodynia, increased the activation of ERK and the production of TNF-α and IL-1β in the TG of WT mice, but not in Cxcr5 (-/-) mice. Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation.

Conclusions: CXCL13 and CXCR5 contribute to orofacial pain via ERK-mediated proinflammatory cytokines production. Targeting CXCL13/CXCR5/ERK/TNF-α and IL-1β pathway in the trigeminal ganglion may offer effective treatment for orofacial neuropathic pain.

Keywords: CXCL13; CXCR5; ERK; Orofacial pain; Proinflammatory cytokines; Trigeminal ganglion.

MeSH terms

  • Activating Transcription Factor 3 / metabolism
  • Animals
  • Chemokine CXCL13 / genetics
  • Chemokine CXCL13 / metabolism*
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Facial Pain / genetics
  • Facial Pain / metabolism*
  • Facial Pain / pathology*
  • Hyperalgesia / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Motor Neurons / metabolism*
  • Pain Measurement
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, CXCR5 / genetics
  • Receptors, CXCR5 / metabolism
  • Signal Transduction / genetics
  • Time Factors
  • Trigeminal Ganglion / pathology*
  • Tubulin / metabolism
  • Up-Regulation / genetics


  • Activating Transcription Factor 3
  • Atf3 protein, mouse
  • CXCR5 protein, mouse
  • Chemokine CXCL13
  • RNA, Small Interfering
  • Receptors, CXCR5
  • Tubulin
  • Extracellular Signal-Regulated MAP Kinases