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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 persistent CXCL13 expression in the TG. a The time course of Cxcl13 mRNA expression in the ipsilateral TG from naïve, sham, and pIONL-operated mice. pIONL increased Cxcl13 expression at 3, 10, and 21 days, compared to sham. *P < 0.05, ***P < 0.001. Two-way ANOVA followed by Bonferroni test. b Western blot shows increased CXCL13 protein level 10 days after pIONL, compared to sham. *P < 0.05. Student’s t test. c Representative images of CXCL13 immunofluorescence in the TG. CXCL13-IR was low in naïve mice (c) and sham mice (d), but increased in the TG of pIONL mice (e). f–h Double staining of CXCL13 (f) and neuronal marker β-III tubulin (g) shows the neuronal expression of CXCL13
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Fig2: pIONL induces persistent CXCL13 expression in the TG. a The time course of Cxcl13 mRNA expression in the ipsilateral TG from naïve, sham, and pIONL-operated mice. pIONL increased Cxcl13 expression at 3, 10, and 21 days, compared to sham. *P < 0.05, ***P < 0.001. Two-way ANOVA followed by Bonferroni test. b Western blot shows increased CXCL13 protein level 10 days after pIONL, compared to sham. *P < 0.05. Student’s t test. c Representative images of CXCL13 immunofluorescence in the TG. CXCL13-IR was low in naïve mice (c) and sham mice (d), but increased in the TG of pIONL mice (e). f–h Double staining of CXCL13 (f) and neuronal marker β-III tubulin (g) shows the neuronal expression of CXCL13

Mentions: We then checked the expression of ATF3, a marker for nerve injury in the ipsilateral TG 10 days after operation. ATF3-immunoreactivity (IR) was not shown in the TG of sham-operated mice (Fig. 1c–e). However, pIONL dramatically increased the percentage of ATF3-IR neurons in the maxillary (V2) division of TG from 0.5 ± 0.1 to 49.8 ± 0.7 % (P < 0.001, Fig. 2c, f, g). The percentage of ATF3-IR cells was not significantly changed in the ophthalmic (V1) division or mandibular (V3) division (P > 0.05, pIONL vs. sham, Fig. 1c). These data confirmed the injury of the second branch of the trigeminal nerve by pIONL.Fig. 2


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 persistent CXCL13 expression in the TG. a The time course of Cxcl13 mRNA expression in the ipsilateral TG from naïve, sham, and pIONL-operated mice. pIONL increased Cxcl13 expression at 3, 10, and 21 days, compared to sham. *P < 0.05, ***P < 0.001. Two-way ANOVA followed by Bonferroni test. b Western blot shows increased CXCL13 protein level 10 days after pIONL, compared to sham. *P < 0.05. Student’s t test. c Representative images of CXCL13 immunofluorescence in the TG. CXCL13-IR was low in naïve mice (c) and sham mice (d), but increased in the TG of pIONL mice (e). f–h Double staining of CXCL13 (f) and neuronal marker β-III tubulin (g) shows the neuronal expression of CXCL13
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4940825&req=5

Fig2: pIONL induces persistent CXCL13 expression in the TG. a The time course of Cxcl13 mRNA expression in the ipsilateral TG from naïve, sham, and pIONL-operated mice. pIONL increased Cxcl13 expression at 3, 10, and 21 days, compared to sham. *P < 0.05, ***P < 0.001. Two-way ANOVA followed by Bonferroni test. b Western blot shows increased CXCL13 protein level 10 days after pIONL, compared to sham. *P < 0.05. Student’s t test. c Representative images of CXCL13 immunofluorescence in the TG. CXCL13-IR was low in naïve mice (c) and sham mice (d), but increased in the TG of pIONL mice (e). f–h Double staining of CXCL13 (f) and neuronal marker β-III tubulin (g) shows the neuronal expression of CXCL13
Mentions: We then checked the expression of ATF3, a marker for nerve injury in the ipsilateral TG 10 days after operation. ATF3-immunoreactivity (IR) was not shown in the TG of sham-operated mice (Fig. 1c–e). However, pIONL dramatically increased the percentage of ATF3-IR neurons in the maxillary (V2) division of TG from 0.5 ± 0.1 to 49.8 ± 0.7 % (P < 0.001, Fig. 2c, f, g). The percentage of ATF3-IR cells was not significantly changed in the ophthalmic (V1) division or mandibular (V3) division (P > 0.05, pIONL vs. sham, Fig. 1c). These data confirmed the injury of the second branch of the trigeminal nerve by pIONL.Fig. 2

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