CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5
CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5
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CXCL13 通过 CXCR5 驱动脊髓星形胶质细胞激活和神经性疼痛
DOI：
10.1172/jci81950
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发表时间：
2016-02-01
影响因子：
15.9
通讯作者：
Gao, Yong-Jing
中科院分区：
文献类型：
--
作者：
Jiang, Bao-Chun;Cao, De-Li;Gao, Yong-Jing
最近的研究表明趋化因子参与了小胶质细胞的活化和神经病理性疼痛的发病机制。C-X-C基序趋化因子13（CXCL 13）是激活CXCRS的B淋巴细胞化学引诱物。使用神经病理性疼痛的脊神经结扎（SNL）模型，我们发现在SNL后，CXCL 13在脊髓神经元中持续上调，导致小鼠脊髓星形胶质细胞通过CXCRS活化。脊髓中CXCL 13的shRNA介导的抑制持续减弱SNL诱导的神经病理性疼痛。有趣的是，CXCL 13的表达被miR-186- 5 p抑制，miR-186- 5 p是一种与CXCL 13共定位的microRNA，在SNL后下调。脊髓过表达miR-186- 5 p可降低CXCL 13表达，减轻神经性疼痛。此外，SNL诱导脊髓星形胶质细胞中的CXCRS表达，并且在Cxcr 5（-/-）小鼠中消除神经性疼痛。SNL诱导的脊髓星形胶质细胞和小胶质细胞活化需要SNL诱导的CXCR 5表达。鞘内注射CXCL 13足以通过CXCR 5和ERK诱导疼痛超敏反应和星形胶质细胞活化。最后，鞘内注射CXCL 13激活的星形胶质细胞诱导幼稚小鼠的机械异常性疼痛。总的来说，我们的研究结果揭示了脊髓中神经元/星形胶质细胞的相互作用，神经元产生的CXCL 13通过CXCRS激活星形胶质细胞以促进神经性疼痛。因此，miR-186- 5 p和CXCL 13/CXCRS介导的星形胶质细胞信号传导可能是神经性疼痛的合适治疗靶点。
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 CXCRS. 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 CXCRS in mice. shRNA-mediated inhibition of CXCL13 in the spinal cord persistently attenuated SNL-induced neuropathii 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 CXCRS 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 CXCRS to facilitate neuropathic pain. Thus, miR-186-5p and CXCL13/CXCRS-mediated astrocyte signaling may be suitable therapeutic targets for neuropathic pain.