CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5
Bao-Chun Jiang, … , Ru-Rong Ji, Yong-Jing Gao
Bao-Chun Jiang, … , Ru-Rong Ji, Yong-Jing Gao
Published January 11, 2016
Citation Information: J Clin Invest. 2016;126(2):745-761. https://doi.org/10.1172/JCI81950.
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CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5

Abstract

Recent studies have implicated chemokines in microglial activation and pathogenesis of neuropathic pain. C-X-C motif chemokine 13 (CXCL13) is a B lymphocyte chemoattractant that activates CXCR5. Using the spinal nerve ligation (SNL) model of neuropathic pain, we found that CXCL13 was persistently upregulated in spinal cord neurons after SNL, resulting in spinal astrocyte activation via CXCR5 in mice. shRNA-mediated inhibition of CXCL13 in the spinal cord persistently attenuated SNL-induced neuropathic pain. Interestingly, CXCL13 expression was suppressed by miR-186-5p, a microRNA that colocalized with CXCL13 and was downregulated after SNL. Spinal overexpression of miR-186-5p decreased CXCL13 expression, alleviating neuropathic pain. Furthermore, SNL induced CXCR5 expression in spinal astrocytes, and neuropathic pain was abrogated in Cxcr5–/– mice. CXCR5 expression induced by SNL was required for the SNL-induced activation of spinal astrocytes and microglia. Intrathecal injection of CXCL13 was sufficient to induce pain hypersensitivity and astrocyte activation via CXCR5 and ERK. Finally, intrathecal injection of CXCL13-activated astrocytes induced mechanical allodynia in naive mice. Collectively, our findings reveal a neuronal/astrocytic interaction in the spinal cord by which neuronally produced CXCL13 activates astrocytes via CXCR5 to facilitate neuropathic pain. Thus, miR-186-5p and CXCL13/CXCR5-mediated astrocyte signaling may be suitable therapeutic targets for neuropathic pain.

Authors

Bao-Chun Jiang, De-Li Cao, Xin Zhang, Zhi-Jun Zhang, Li-Na He, Chun-Hua Li, Wen-Wen Zhang, Xiao-Bo Wu, Temugin Berta, Ru-Rong Ji, Yong-Jing Gao

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Figure 3

miR-186-5p inhibits neuropathic pain via suppressing CXCL13 expression in the spinal cord.

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miR-186-5p inhibits neuropathic pain via suppressing CXCL13 expression i...
(A and B) Intraspinal infusion of mmu-pre-miR-186 expressing lentivirus 3 days after SNL alleviated SNL-induced mechanical allodynia (A) and heat hyperalgesia (B) at days 7, 10, and 14. *P < 0.05; ***P < 0.001, 2-way repeated measures ANOVA followed by Bonferroni’s test. n = 7 for LV-NC; n = 8 for SNL or LV-pre-mmu-miR-186 group. BL, baseline. (C and D) Injection (i.t.) of miR-186-5p mimic daily for 3 days (from day 8 to day 10 after SNL) attenuated SNL-induced mechanical allodynia (C) and heat hyperalgesia (D). **P < 0.01, ***P < 0.001, 2-way repeated measures ANOVA followed by Bonferroni’s test. n = 9 for NC and n = 10 for miR-186 mimic. (E) ELISA results show decreased CXCL13 levels in the spinal cord of miR-186-5p mimic–treated animals. *P < 0.05, Student’s t test. n = 6 mice/group. (F and G) Injection (i.t.) of miR-186-5p inhibitor induced mechanical allodynia (F) and heat hyperalgesia (G) in naive mice. *P < 0.05; **P < 0.01; ***P < 0.001, miR-186-5p inhibitor vs. NC, 2-way repeated measures ANOVA followed by Bonferroni’s test. n = 5 mice/group. (H) CXCL13 neutralizing antibody attenuated miR-186-5p inhibitor–induced mechanical allodynia. *P < 0.05, 2-way repeated measures ANOVA followed by Bonferroni’s test. n = 5 mice/group. (I) Injection (i.t.) of MK801 before SNL prevented SNL-induced downregulation of miR-186-5p in the spinal cord. *P < 0.05; **P < 0.01, 1-way ANOVA followed by Bonferroni’s test. n = 5 mice/group. (J) Injection (i.t.) MK801 also inhibited SNL-induced upregulation of CXCL13. *P < 0.05, 1-way ANOVA followed by Bonferroni’s test. n = 4–6 mice/group. (K) Injection (i.t.) of NMDA in naive mice decreased miR-186-5p expression. *P < 0.05, Student’s t test. n = 4–5 mice/group. (L) Injection (i.t.) NMDA also increased CXCL13 expression. *P < 0.05, Student’s t test. n = 6 mice/group.