TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG.
TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG.
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TLR8 及其内源性配体 miR-21 导致小鼠 DRG 中的神经性疼痛
DOI：
10.1084/jem.20180800
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发表时间：
2018-12-03
期刊：
影响因子：
--
通讯作者：
Gao YJ
中科院分区：
文献类型：
--
作者：
Zhang ZJ;Guo JS;Li SS;Wu XB;Cao DL;Jiang BC;Jing PB;Bai XQ;Li CH;Wu ZH;Lu Y;Gao YJ
已知TLR对于先天性和适应性免疫是必需的。Zhang等人显示了TLR 8及其内源性配体miR-21通过诱导DRG中ERK依赖性促炎介质的产生和神经元过度兴奋而参与神经性疼痛。Toll样受体（TLR）是核酸敏感受体，并且已经涉及介导疼痛和瘙痒。在这里，我们报告说，Tlr 8 −/−小鼠表现出正常的瘙痒行为，但在小鼠脊神经结扎（SNL）诱导的神经性疼痛中存在缺陷。SNL增加小直径IB 4 + DRG神经元TLR 8表达。抑制DRG中的TLR 8可减弱SNL诱导的疼痛超敏反应。相反，鞘内或皮内注射TLR 8激动剂VTX-2337，诱导TLR 8依赖性疼痛超敏反应。TLR 8定位于核内体和溶酶体，介导ERK激活、炎症介质的产生和SNL后神经元的过度兴奋。值得注意的是，SNL后DRG神经元中的miR-21增加。鞘内注射miR-21显示出与VTX-2337相似的作用，并且在DRG中抑制miR-21减轻了神经病理性疼痛。目前的研究揭示了TLR 8在维持神经性疼痛中的一个先前未知的作用，这表明miR-21-TLR 8信号传导可能是针对这种类型的慢性疼痛的药物开发的潜在新靶点。
TLRs are known to be essential for innate and adaptive immunity. Zhang et al. show the involvement of TLR8 and its endogenous ligand miR-21 in neuropathic pain via inducing ERK-dependent proinflammatory mediators’ production and neuronal hyperexcitability in the DRG. Toll-like receptors (TLRs) are nucleic acid–sensing receptors and have been implicated in mediating pain and itch. Here we report that Tlr8−/− mice show normal itch behaviors, but have defects in neuropathic pain induced by spinal nerve ligation (SNL) in mice. SNL increased TLR8 expression in small-diameter IB4+ DRG neurons. Inhibition of TLR8 in the DRG attenuated SNL-induced pain hypersensitivity. Conversely, intrathecal or intradermal injection of TLR8 agonist, VTX-2337, induced TLR8-dependent pain hypersensitivity. Mechanistically, TLR8, localizing in the endosomes and lysosomes, mediated ERK activation, inflammatory mediators’ production, and neuronal hyperexcitability after SNL. Notably, miR-21 was increased in DRG neurons after SNL. Intrathecal injection of miR-21 showed the similar effects as VTX-2337 and inhibition of miR-21 in the DRG attenuated neuropathic pain. The present study reveals a previously unknown role of TLR8 in the maintenance of neuropathic pain, suggesting that miR-21–TLR8 signaling may be potential new targets for drug development against this type of chronic pain.
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影响因子：
3.7
作者：
Itoh H;Tatematsu M;Watanabe A;Iwano K;Funami K;Seya T;Matsumoto M
通讯作者：
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影响因子：
64.8
作者：
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DOI：
10.1073/pnas.1209414109
发表时间：
2012-07-31
影响因子：
11.1
作者：
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通讯作者：
Croce, Carlo M.
影响因子：
7.4
作者：
Christianson CA;Dumlao DS;Stokes JA;Dennis EA;Svensson CI;Corr M;Yaksh TL
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影响因子：
5.3
作者：
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通讯作者：
Sarret, Philippe