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

Zhang Q, Cao DL, Zhang ZJ, Jiang BC, Gao YJ - J Neuroinflammation (2016)

Bottom Line: The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing. pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG.Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL.Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation.

View Article: PubMed Central - PubMed

Affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Seyuan Road, Nantong, Jiangsu, 226019, China.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

pIONL induces the activation of ERK in the TG. a Western blot shows the expression of pERK in naive, sham, and pIONL mice. pIONL increased the expression of pERK expression in WT mice, and the increase was reduced in Cxcr5 KO mice. *P < 0.05. One-way ANOVA followed by Bonferroni test (left histogram) or Student’s t test (right histogram). b Representative images of pERK immunofluorescence in the TG of WT and KO mice 10 days after the operation. pERK-IR was increased after pIONL in WT mice, but not in KO mice
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Fig6: pIONL induces the activation of ERK in the TG. a Western blot shows the expression of pERK in naive, sham, and pIONL mice. pIONL increased the expression of pERK expression in WT mice, and the increase was reduced in Cxcr5 KO mice. *P < 0.05. One-way ANOVA followed by Bonferroni test (left histogram) or Student’s t test (right histogram). b Representative images of pERK immunofluorescence in the TG of WT and KO mice 10 days after the operation. pERK-IR was increased after pIONL in WT mice, but not in KO mice

Mentions: Our recent study showed that ERK is an important downstream of CXCL13/CXCR5 signaling in the spinal cord [11]. We then checked the activation of ERK in the TG after pIONL. Western blot showed that, compared to naive or sham-operated animals, pIONL increased pERK expression in the TG 10 days after pIONL (P < 0.05, vs. naïve or sham, one-way ANOVA followed by Bonferroni test, Fig. 6a). In addition, pERK expression was comparable between WT and Cxcr5 KO mice after sham operation, but pERK was significantly reduced in KO mice after pIONL (P < 0.05, vs. WT, Student’s t test). Immunostaining showed that pERK had low expression in WT mice after sham operation, but was increased in WT mice after pIONL. However, similar expression of pERK was observed in both sham-operated and pIONL KO mice (Fig. 6b).Fig. 6


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

Zhang Q, Cao DL, Zhang ZJ, Jiang BC, Gao YJ - J Neuroinflammation (2016)

pIONL induces the activation of ERK in the TG. a Western blot shows the expression of pERK in naive, sham, and pIONL mice. pIONL increased the expression of pERK expression in WT mice, and the increase was reduced in Cxcr5 KO mice. *P < 0.05. One-way ANOVA followed by Bonferroni test (left histogram) or Student’s t test (right histogram). b Representative images of pERK immunofluorescence in the TG of WT and KO mice 10 days after the operation. pERK-IR was increased after pIONL in WT mice, but not in KO mice
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Related In: Results  -  Collection

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Fig6: pIONL induces the activation of ERK in the TG. a Western blot shows the expression of pERK in naive, sham, and pIONL mice. pIONL increased the expression of pERK expression in WT mice, and the increase was reduced in Cxcr5 KO mice. *P < 0.05. One-way ANOVA followed by Bonferroni test (left histogram) or Student’s t test (right histogram). b Representative images of pERK immunofluorescence in the TG of WT and KO mice 10 days after the operation. pERK-IR was increased after pIONL in WT mice, but not in KO mice
Mentions: Our recent study showed that ERK is an important downstream of CXCL13/CXCR5 signaling in the spinal cord [11]. We then checked the activation of ERK in the TG after pIONL. Western blot showed that, compared to naive or sham-operated animals, pIONL increased pERK expression in the TG 10 days after pIONL (P < 0.05, vs. naïve or sham, one-way ANOVA followed by Bonferroni test, Fig. 6a). In addition, pERK expression was comparable between WT and Cxcr5 KO mice after sham operation, but pERK was significantly reduced in KO mice after pIONL (P < 0.05, vs. WT, Student’s t test). Immunostaining showed that pERK had low expression in WT mice after sham operation, but was increased in WT mice after pIONL. However, similar expression of pERK was observed in both sham-operated and pIONL KO mice (Fig. 6b).Fig. 6

Bottom Line: The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing. pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG.Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL.Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation.

View Article: PubMed Central - PubMed

Affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Seyuan Road, Nantong, Jiangsu, 226019, China.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus