Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of postherpetic neuralgia (PHN). The immune escape mechanism of VZV remains to be elusive. Due to mice have no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well-established PHN mice model. Transcriptional expression analysis identified that the protein arginine methyltransferases 6 (Prmt6) was upregulated upon HSV-1 infection, which was further confirmed by immunofluorescence staining in spinal dorsal horn. Prmt6 deficiency decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load in vivo and in vitro. Overexpression of Prmt6 in microglia dampened antiviral innate immunity and increased HSV-1 load. Mechanistically, Prmt6 methylated and inactivated STING, resulting in reduced phosphorylation of TANK binding kinase-1 (TBK1) and interferon regulatory factor 3 (IRF3), diminished production of type I interferon (IFN-I) and antiviral innate immunity. Furthermore, intrathecal or intraperitoneal administration of the Prmt6 inhibitor EPZ020411 decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load. Our findings revealed that HSV-1 escapes antiviral innate immunity and results in PHN by upregulating Prmt6 expression and inhibiting cGAS-STING pathway, providing novel insights and a potential therapeutic target for PHN.

中文翻译：

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HSV-1 重新激活通过上调 Prmt6 和抑制 cGAS-STING 导致带状疱疹后神经痛

慢性水痘带状疱疹病毒（VZV）感染引起的神经炎症是带状疱疹后神经痛（PHN）的关键病理。VZV 的免疫逃逸机制仍不清楚。由于小鼠没有 VZV 感染受体，1 型单纯疱疹病毒 (HSV-1) 感染是一种成熟的 PHN 小鼠模型。转录表达分析发现，HSV-1 感染后蛋白质精氨酸甲基转移酶 6 (Prmt6) 上调，脊髓背角免疫荧光染色进一步证实了这一点。Prmt6 缺陷通过增强抗病毒先天免疫和降低体内和体外 HSV-1 负荷来减少 HSV-1 诱导的神经炎症和 PHN。小胶质细胞中 Prmt6 的过度表达会抑制抗病毒先天免疫并增加 HSV-1 负载。从机制上讲，Prmt6 甲基化并使 STING 失活，导致 TANK 结合激酶 1 (TBK1) 和干扰素调节因子 3 (IRF3) 的磷酸化减少，I 型干扰素 (IFN-I) 的产生和抗病毒先天免疫减少。此外，鞘内或腹膜内施用 Prmt6 抑制剂 EPZ020411 通过增强抗病毒先天免疫和降低 HSV-1 负荷，减少 HSV-1 诱导的神经炎症和 PHN。我们的研究结果表明，HSV-1 通过上调 Prmt6 表达和抑制 cGAS-STING 通路来逃避抗病毒先天免疫并导致 PHN，这为 PHN 提供了新的见解和潜在的治疗靶点。