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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-induced mechanical allodynia is mediated by ERK-dependent proinflammatory cytokines production in the TG. a pIONL increased TNF-α and IL-1β expression 10 days after pIONL in WT mice, but not in Cxcr5 KO mice. *P < 0.05, ***P < 0.001. One-way ANOVA followed by Bonferroni test. b Intra-TG injection of MEK inhibitor, PD98059 10 days after pIONL attenuated pIONL-induced mechanical allodynia at 3 h. **P < 0.01. Two-way repeated measures ANOVA followed by Bonferroni test. The same treatment reduced the expression of TNF-α (c) and IL-1β (d). **P < 0.01, Student’s t test. e Intra-TG injection of TNF-α inhibitor, Etanercept 10 days after pIONL alleviated pIONL-induced mechanical allodynia. The effect was shown 1 h after injection and maintained for more than 6 h. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. f Intra-TG injection of IL-1β inhibitor, Diacerein 10 days after pIONL alleviated pIONL-induced mechanical allodynia from 1 to 6 h. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test
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Fig7: pIONL-induced mechanical allodynia is mediated by ERK-dependent proinflammatory cytokines production in the TG. a pIONL increased TNF-α and IL-1β expression 10 days after pIONL in WT mice, but not in Cxcr5 KO mice. *P < 0.05, ***P < 0.001. One-way ANOVA followed by Bonferroni test. b Intra-TG injection of MEK inhibitor, PD98059 10 days after pIONL attenuated pIONL-induced mechanical allodynia at 3 h. **P < 0.01. Two-way repeated measures ANOVA followed by Bonferroni test. The same treatment reduced the expression of TNF-α (c) and IL-1β (d). **P < 0.01, Student’s t test. e Intra-TG injection of TNF-α inhibitor, Etanercept 10 days after pIONL alleviated pIONL-induced mechanical allodynia. The effect was shown 1 h after injection and maintained for more than 6 h. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. f Intra-TG injection of IL-1β inhibitor, Diacerein 10 days after pIONL alleviated pIONL-induced mechanical allodynia from 1 to 6 h. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test

Mentions: We further checked the downstream of ERK underlying pIONL-induced orofacial mechanical allodynia. TNF-α and IL-1β are important proinflammatory cytokines in regulating chronic pain in both peripheral nervous system and central nervous system [26]. We checked TNF-α and IL-1β mRNA expression in the TG 10 days after pIONL or sham operation. As shown in Fig. 7a, pIONL increased TNF-α and IL-1β mRNA expression in the TG of WT mice (TNF-α, P < 0.05; IL-1β, P < 0.001, pIONL vs. sham), but not in KO mice. These data suggest that pIONL induces CXCR5-dependent TNF-α and IL-1β expression.Fig. 7


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-induced mechanical allodynia is mediated by ERK-dependent proinflammatory cytokines production in the TG. a pIONL increased TNF-α and IL-1β expression 10 days after pIONL in WT mice, but not in Cxcr5 KO mice. *P < 0.05, ***P < 0.001. One-way ANOVA followed by Bonferroni test. b Intra-TG injection of MEK inhibitor, PD98059 10 days after pIONL attenuated pIONL-induced mechanical allodynia at 3 h. **P < 0.01. Two-way repeated measures ANOVA followed by Bonferroni test. The same treatment reduced the expression of TNF-α (c) and IL-1β (d). **P < 0.01, Student’s t test. e Intra-TG injection of TNF-α inhibitor, Etanercept 10 days after pIONL alleviated pIONL-induced mechanical allodynia. The effect was shown 1 h after injection and maintained for more than 6 h. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. f Intra-TG injection of IL-1β inhibitor, Diacerein 10 days after pIONL alleviated pIONL-induced mechanical allodynia from 1 to 6 h. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test
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Fig7: pIONL-induced mechanical allodynia is mediated by ERK-dependent proinflammatory cytokines production in the TG. a pIONL increased TNF-α and IL-1β expression 10 days after pIONL in WT mice, but not in Cxcr5 KO mice. *P < 0.05, ***P < 0.001. One-way ANOVA followed by Bonferroni test. b Intra-TG injection of MEK inhibitor, PD98059 10 days after pIONL attenuated pIONL-induced mechanical allodynia at 3 h. **P < 0.01. Two-way repeated measures ANOVA followed by Bonferroni test. The same treatment reduced the expression of TNF-α (c) and IL-1β (d). **P < 0.01, Student’s t test. e Intra-TG injection of TNF-α inhibitor, Etanercept 10 days after pIONL alleviated pIONL-induced mechanical allodynia. The effect was shown 1 h after injection and maintained for more than 6 h. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test. f Intra-TG injection of IL-1β inhibitor, Diacerein 10 days after pIONL alleviated pIONL-induced mechanical allodynia from 1 to 6 h. *P < 0.05, ***P < 0.001. Two-way repeated measures ANOVA followed by Bonferroni test
Mentions: We further checked the downstream of ERK underlying pIONL-induced orofacial mechanical allodynia. TNF-α and IL-1β are important proinflammatory cytokines in regulating chronic pain in both peripheral nervous system and central nervous system [26]. We checked TNF-α and IL-1β mRNA expression in the TG 10 days after pIONL or sham operation. As shown in Fig. 7a, pIONL increased TNF-α and IL-1β mRNA expression in the TG of WT mice (TNF-α, P < 0.05; IL-1β, P < 0.001, pIONL vs. sham), but not in KO mice. These data suggest that pIONL induces CXCR5-dependent TNF-α and IL-1β expression.Fig. 7

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