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.
View: Text | PDF
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

×

Figure 10

Schematic shows spinal neuronal-glial interactions in neuropathic pain after peripheral nerve injury.

Options: View larger image (or click on image) Download as PowerPoint
Schematic shows spinal neuronal-glial interactions in neuropathic pain a...
(A) Neuronal-glial interactions revealed in previous studies. After nerve injury, CCL2 and CX3CL1 are released from the central terminals of primary afferent neurons (presynaptic sites) and spinal neurons (postsynaptic sites), which activate CCR2 and CX3CR1, respectively, on spinal microglia. CCL2 and CXCL1 can be released from astrocytes to act on spinal neurons via CCR2 and CXCR2, respectively. Astrocytes may also produce CCL7 to recognize CCR2 on microglia. Upon activation, microglia produce cytokines TNF-α and IL-18 to activate astrocytes via TNFR and IL-18R. Microglia also produce the neurotrophin brain-derived neurotrophic factor (BDNF) via P2X4 activation to enhance nociceptive synaptic transmission (63, 68). (B) Neuronal-glial interactions revealed in the present study. SNL increases glutamate release from presynaptic terminals to activate NMDAR on postsynaptic neurons, leading to decreased expression of miR-186-5p, and this decrease results in CXCL13 upregulation in spinal neurons. Upon release, CXCL13 acts on CXCR5 in astrocytes and activates the ERK signaling pathway, leading to the expression and release of astroglial mediators, such as CCL2 and CCL7, to maintain microglial activation. Astrocytes may also produce ATP to activate microglia via P2X4, P2X7, and P2Y12 receptors (47, 63, 69). These astrocytic mediators can also directly potentiate nociceptive transmission via pre- and postsynaptic modulation (10, 52). Together, this CXCL13-CXCR5–mediated neuronal-astrocytic interaction in the dorsal horn can enhance and prolong neuropathic pain states.