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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Research Article Neuroscience

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 7

Injection (i.t.) of CXCL13 induces pain hypersensitivity and glial activation in the spinal cord.

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Injection (i.t.) of CXCL13 induces pain hypersensitivity and glial activ...
(A) Injection (i.t.) of CXCL13 induced heat hyperalgesia in WT mice, but not in Cxcr5 KO mice. ***P < 0.001, WT vehicle (n = 7) vs. WT CXL13 (n = 7). ###P < 0.001, WT CXCL13 (n = 7) vs. Cxcr5–/– CXCL13 (n = 7), 2-way repeated measures ANOVA followed by Bonferroni’s test. (B) Injection (i.t.) of CXCL13 induced mechanical allodynia in WT mice, which was reduced in KO mice. ***P < 0.001, WT vehicle vs. WT CXL13. #P < 0.05; ##P < 0.01; ###P < 0.001, WT-CXCL13 vs. Cxcr5–/–-CXCL13, 2-way repeated measures ANOVA followed by Bonferroni’s test. (C) Injection (i.t.) of CXCL13 increased Gfap mRNA at 6 hours and Iba1 mRNA at 24 hours. **P < 0.01; ***P < 0.001 vs. control, 1-way ANOVA followed by Bonferroni’s test. n = 4–7 mice/group. (D–H) Injection (i.t.) of CXCL13 increased GFAP IR in WT mice, but not in Cxcr5 KO mice 6 hours after injection. ***P < 0.001, Student’s t test. n = 4 mice/group. Scale bars: 100 μm. (I) Pretreatment with astroglial toxin L-α-AA blocked CXCL13-induced heat hyperalgesia. Pretreatment with microglial inhibitor minocycline attenuated heat hyperalgesia at 24 hours. *P < 0.05; ***P < 0.001, 2-way repeated measures ANOVA followed by Bonferroni’s test. n = 5 mice/group. (J) Pretreatment with L-α-AA inhibited CXCL13-induced mechanical allodynia. *P < 0.05, 2-way repeated measures ANOVA followed by Bonferroni’s test. n = 5–8 mice/group. (K) L-α-AA and minocycline decreased CXCL13-induced Iba1 mRNA upregulation in the spinal cord 24 hours after CXCL13 injection. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA followed by Bonferroni’s test. n = 3–6 mice/group. Veh, vehicle.