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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

Intra-TG injection of CXCL13 induces CXCR5/ERK-dependent mechanical allodynia and proinflammatory cytokines production. a, b Intra-TG injection of CXCL13 (100 ng) induced mechanical allodynia in WT mice (a), but not in Cxcr5 KO mice (b). ***P < 0.001, WT-vehicle vs. WT-CXL13. Two-way repeated measures ANOVA followed by Bonferroni test. c Western blot showing that intra-TG CXCL13 significantly increased pERK expression in the TG in WT mice, but not in Cxcr5 KO mice. *P < 0.05. Student’s t test. d Intra-TG injection of CXCL13 increases TNF-α and IL-1β expression at 1 and 3 h in WT mice, but not in Cxcr5 KO mice. *P < 0.05, **P < 0.01. One-way ANOVA followed by Bonferroni test. e Intra-TG injection of PD98059, Etanercept, or Diacerein partially blocked intra-TG CXCL13-induced mechanical allodynia. *P < 0.05, **P < 0.01, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test
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Fig8: Intra-TG injection of CXCL13 induces CXCR5/ERK-dependent mechanical allodynia and proinflammatory cytokines production. a, b Intra-TG injection of CXCL13 (100 ng) induced mechanical allodynia in WT mice (a), but not in Cxcr5 KO mice (b). ***P < 0.001, WT-vehicle vs. WT-CXL13. Two-way repeated measures ANOVA followed by Bonferroni test. c Western blot showing that intra-TG CXCL13 significantly increased pERK expression in the TG in WT mice, but not in Cxcr5 KO mice. *P < 0.05. Student’s t test. d Intra-TG injection of CXCL13 increases TNF-α and IL-1β expression at 1 and 3 h in WT mice, but not in Cxcr5 KO mice. *P < 0.05, **P < 0.01. One-way ANOVA followed by Bonferroni test. e Intra-TG injection of PD98059, Etanercept, or Diacerein partially blocked intra-TG CXCL13-induced mechanical allodynia. *P < 0.05, **P < 0.01, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test

Mentions: To investigate whether CXCL13 is sufficient to induce orofacial pain, we injected CXCL13 into the TG in WT and Cxcr5 KO mice. As shown in Fig. 8a, CXCL13 (100 ng), but not vehicle (PBS)-induced mechanical allodynia in WT mice for more than 6 h (P < 0.001, two-way repeated measures ANOVA), whereas Cxcr5 KO mice failed to develop the mechanical allodynia by CXCL13 (Fig. 8b).Fig. 8


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)

Intra-TG injection of CXCL13 induces CXCR5/ERK-dependent mechanical allodynia and proinflammatory cytokines production. a, b Intra-TG injection of CXCL13 (100 ng) induced mechanical allodynia in WT mice (a), but not in Cxcr5 KO mice (b). ***P < 0.001, WT-vehicle vs. WT-CXL13. Two-way repeated measures ANOVA followed by Bonferroni test. c Western blot showing that intra-TG CXCL13 significantly increased pERK expression in the TG in WT mice, but not in Cxcr5 KO mice. *P < 0.05. Student’s t test. d Intra-TG injection of CXCL13 increases TNF-α and IL-1β expression at 1 and 3 h in WT mice, but not in Cxcr5 KO mice. *P < 0.05, **P < 0.01. One-way ANOVA followed by Bonferroni test. e Intra-TG injection of PD98059, Etanercept, or Diacerein partially blocked intra-TG CXCL13-induced mechanical allodynia. *P < 0.05, **P < 0.01, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test
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Fig8: Intra-TG injection of CXCL13 induces CXCR5/ERK-dependent mechanical allodynia and proinflammatory cytokines production. a, b Intra-TG injection of CXCL13 (100 ng) induced mechanical allodynia in WT mice (a), but not in Cxcr5 KO mice (b). ***P < 0.001, WT-vehicle vs. WT-CXL13. Two-way repeated measures ANOVA followed by Bonferroni test. c Western blot showing that intra-TG CXCL13 significantly increased pERK expression in the TG in WT mice, but not in Cxcr5 KO mice. *P < 0.05. Student’s t test. d Intra-TG injection of CXCL13 increases TNF-α and IL-1β expression at 1 and 3 h in WT mice, but not in Cxcr5 KO mice. *P < 0.05, **P < 0.01. One-way ANOVA followed by Bonferroni test. e Intra-TG injection of PD98059, Etanercept, or Diacerein partially blocked intra-TG CXCL13-induced mechanical allodynia. *P < 0.05, **P < 0.01, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test
Mentions: To investigate whether CXCL13 is sufficient to induce orofacial pain, we injected CXCL13 into the TG in WT and Cxcr5 KO mice. As shown in Fig. 8a, CXCL13 (100 ng), but not vehicle (PBS)-induced mechanical allodynia in WT mice for more than 6 h (P < 0.001, two-way repeated measures ANOVA), whereas Cxcr5 KO mice failed to develop the mechanical allodynia by CXCL13 (Fig. 8b).Fig. 8

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