Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development
Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development
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DOI：
10.1038/emboj.2011.89
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发表时间：
2011-05-04
期刊：
影响因子：
11.4
通讯作者：
Inoue, Kazuhide
中科院分区：
文献类型：
--
作者：
Biber, Knut;Tsuda, Makoto;Inoue, Kazuhide
脊髓小胶质细胞中P2 X4受体的上调对于触觉异常性疼痛至关重要，触觉异常性疼痛是周围神经损伤后发生的一种无法治疗的病理性疼痛反应。外周神经损伤如何导致脊髓背角的小胶质细胞反应尚不清楚。这里显示，CCL 21在受损的小型初级感觉神经元中迅速表达，并被转运到它们在背角中的中央终末。鞘内注射CCL 21阻断抗体可减少野生型动物触觉异常性疼痛的发生。缺乏CCL 21的小鼠没有出现任何触觉异常性疼痛的迹象，也没有上调小胶质细胞P2 X4受体的表达。在体外和体内，CCL 21应用增强小胶质细胞P2 X4表达。单次鞘内注射CCL 21神经损伤的CCL 21缺陷型小鼠诱导持久的异常性疼痛，这是无法区分的野生型反应。CCL 21注射的这种作用严格依赖于P2 X4受体功能。由于神经元CCL 21是导致触觉异常性疼痛的级联反应中最早被鉴定的因子，这些发现可能导致神经病理性疼痛的预防性治疗。The EMBO Journal（2011）30，1864-1873. doi：10.1038/daj.2011.89; 2011年3月25日在线发布
Up-regulation of P2X4 receptors in spinal cord microglia is crucial for tactile allodynia, an untreatable pathological pain reaction occurring after peripheral nerve injury. How nerve injury in the periphery leads to this microglia reaction in the dorsal horn of the spinal cord is not yet understood. It is shown here that CCL21 was rapidly expressed in injured small-sized primary sensory neurons and transported to their central terminals in the dorsal horn. Intrathecal administration of a CCL21-blocking antibody diminished tactile allodynia development in wildtype animals. Mice deficient for CCL21 did not develop any signs of tactile allodynia and failed to up-regulate microglial P2X4 receptor expression. Microglia P2X4 expression was enhanced by CCL21 application in vitro and in vivo. A single intrathecal injection of CCL21 to nerve-injured CCL21-deficient mice induced long-lasting allodynia that was undistinguishable from the wild-type response. This effect of CCL21 injection was strictly dependent on P2X4 receptor function. Since neuronal CCL21 is the earliest yet identified factor in the cascade leading to tactile allodynia, these findings may lead to a preventive therapy in neuropathic pain. The EMBO Journal (2011) 30, 1864-1873. doi:10.1038/emboj.2011.89; Published online 25 March 2011