SETD7 mediates spinal microgliosis and neuropathic pain in a rat model of peripheral nerve injury
SETD7 mediates spinal microgliosis and neuropathic pain in a rat model of peripheral nerve injury
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SETD7 在周围神经损伤大鼠模型中介导脊髓小胶质细胞增生和神经性疼痛
DOI：
10.1016/j.bbi.2019.09.007
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发表时间：
2019-11-01
影响因子：
15.1
通讯作者：
Huang, Changsheng
中科院分区：
文献类型：
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作者：
Shen, Yu;Ding, Zhuofeng;Huang, Changsheng
基因转录调控在周围神经损伤后脊髓小胶质细胞增多症和神经病理性疼痛的发生发展中起关键作用。本研究利用坐骨神经慢性压迫性损伤(CCI)模型，研究了含有赖氨酸甲基转移酶7(SETD7)的SET结构域(SETD7)对组蛋白H3赖氨酸4(H3K4me1)单甲基化的作用。CCI后1d~14d，损伤侧脊髓背角SETD7蛋白表达增加，同时伴有炎症基因CCL2、IL-6和IL-1β的表达。免疫组织化学和免疫印迹显示CCI诱导的SETD7表达主要定位于小胶质细胞。在CCI前鞘内注射慢病毒shRNA抑制SETD7基因，可预防脊髓小胶质细胞增多症和神经病理性疼痛，而慢病毒SETD7转导可加重这些症状。此外，SETD7还调节CCI大鼠和Hapi大鼠小胶质细胞H3K4me1水平和炎症介质的表达。相应地，SETD7单甲基化活性的特异性抑制剂PFI-2抑制了脂多糖诱导的原代小胶质细胞的阿米巴样形态和炎症基因CCL2、IL-6和IL-1β的表达。此外，鞘内注射PFI-2可减轻CCI诱导的神经病理性疼痛。然而，这种影响在雄性大鼠身上观察到，而在雌性大鼠身上观察不到。这些结果表明SETD7在脊髓小胶质细胞增多症和随后的周围神经损伤的神经病理性疼痛的发展中起关键作用。药理学方法进一步表明，SETD7是治疗神经病理性疼痛的新靶点。其机制可能与H3K4me1对小胶质细胞炎症基因表达的调控有关。
Gene transcription regulation is critical for the development of spinal microgliosis and neuropathic pain after peripheral nerve injury. Using a model of chronic constriction injury (CCI) of the sciatic nerve, this study characterized the role of SET domain containing lysine methyltransferase 7 (SETD7) which monomethylates histone H3 lysine 4 (H3K4me1), a marker for active gene transcription. SETD7 protein expression in the spinal dorsal horn ipsilateral to nerve lesion was increased from one day to 14 days after CCI, concomitantly with the expression of inflammatory genes, Ccl2, Il-6 and Il-1 beta. The CCI-induced SETD7 expression was predominantly localized to microglia, as demonstrated by immunohistochentistry and western blot from magnetic activated cell sorted spinal microglia. SETD7 knockdown by intrathecal lentivirus shRNA delivery prior to CCI prevented spinal microgliosis and neuropathic pain, whereas lentiviral SETD7 transduction exacerbated these symptoms. In addition, SETD7 regulated H3K4me1 level and expression of inflammatory mediators both in CCI rats and in the HAPI rat microglia cell line. Accordingly, PFI-2, a specific inhibitor of SETD7 monomethylation activity, suppressed the lipopolysaccharides-induced amoeboid morphology of primary microglia and the expression of inflammatory genes, Ccl2, Il-6 and Il-1 beta. Moreover, intrathecal administration of PFI-2 alleviated CCI-induced neuropathic pain. However, this effect was observed in male but not in female rats. These results demonstrate a critical role of SETD7 in the development of spinal microgliosis and neuropathic pain subsequently to peripheral nerve injury. The pharmacological approach further suggests that SETD7 is a new target for the treatment of neuropathic pain. The underlying mechanisms may involve H3K4me1-dependent regulation of inflammatory gene expression in microglia.