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<p>Postherpetic neuralgia (PHN) is characterized by neural injury and neuroinflammation resulting from viral infection and reactivation. Herpes simplex virus type 1 (HSV-1) is capable of inducing virus-associated PHN-like neuropathic pain and has been widely used as a model for studying virus-induced neuroinflammatory pain. However, the immune mechanisms underlying virus-induced neuroinflammation and pain remain incompletely understood. In this study, we used an HSV-1-induced neuroinflammatory pain model and observed reduced <i>Lapf</i> expression following HSV-1 infection through transcriptome sequencing, which was further confirmed to be localized in microglia of the spinal dorsal horn by immunofluorescence staining. <i>Lapf</i> microglia-specific deficiency aggravated neuroinflammation and promoted mechanical allodynia by impairing antiviral innate immunity both in vivo and in vitro. Overexpression of <i>Lapf</i> in microglia strengthened antiviral innate immunity and suppressed HSV-1 replication. Mechanistically, transcriptome sequencing of <i>Lapf</i> microglia-specific deficient mice identified lysosomal endocytosis as a critical pathway in LAPF-mediated antiviral innate immunity. <i>Lapf</i> deficiency decreased lysosomal acidity, resulting in reduced TLR9 activation, thereby impairing viral DNA sensing and IFN-I production. <i>Lapf</i> deficiency also reduced lysosomal membrane stability, facilitating the escape of HSV-1 DNA into the cytoplasm, where it could amplify and reactivate. Conversely, <i>Lapf</i> overexpression enhanced lysosomal acidity and membrane stability, promoting TLR9 activation and antiviral innate immunity. Furthermore, <i>Lapf</i> deficiency markedly reduced the phosphorylation of STING, TBK1, and IRF3, whereas <i>Lapf</i> overexpression restored cGAS-STING signaling. This effect was abolished by lysosomal acidification inhibitor chloroquine (CQ), supporting that LAPF promotes lysosomal acidification-dependent antiviral immunity via TLR9 and cGAS-STING pathways. Pharmacological enhancement of LAPF activity using the dephosphorylation inhibitor SHP099 alleviated neuroinflammation and mechanical allodynia in HSV-1-induced neuroinflammatory pain model mice, suggesting potential therapeutic implications. In conclusion, our findings demonstrate that LAPF enhances lysosomal acidification to promote dual antiviral innate immune responses via TLR9 and cGAS-STING pathways in HSV-1 infection, thereby attenuating HSV-1-induced neuroinflammatory pain. These results provide mechanistic insights and potential therapeutic targets for virus-associated neuroinflammatory pain.</p>

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LAPF enhances lysosomal acidification to promote TLR9 and cGAS-STING-mediated antiviral immunity and attenuate HSV-1-induced neuroinflammatory pain

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月8日

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  • Erliang Kong,
  • Mengqiu Deng,
  • Ruifeng Ding,
  • Mei Yang,
  • Yongchang Li,
  • Xudong Feng,
  • Honghao Song,
  • Huawei Wei,
  • Xin Jiang,
  • Hongbin Yuan,
  • Chaofeng Han

摘要

Postherpetic neuralgia (PHN) is characterized by neural injury and neuroinflammation resulting from viral infection and reactivation. Herpes simplex virus type 1 (HSV-1) is capable of inducing virus-associated PHN-like neuropathic pain and has been widely used as a model for studying virus-induced neuroinflammatory pain. However, the immune mechanisms underlying virus-induced neuroinflammation and pain remain incompletely understood. In this study, we used an HSV-1-induced neuroinflammatory pain model and observed reduced Lapf expression following HSV-1 infection through transcriptome sequencing, which was further confirmed to be localized in microglia of the spinal dorsal horn by immunofluorescence staining. Lapf microglia-specific deficiency aggravated neuroinflammation and promoted mechanical allodynia by impairing antiviral innate immunity both in vivo and in vitro. Overexpression of Lapf in microglia strengthened antiviral innate immunity and suppressed HSV-1 replication. Mechanistically, transcriptome sequencing of Lapf microglia-specific deficient mice identified lysosomal endocytosis as a critical pathway in LAPF-mediated antiviral innate immunity. Lapf deficiency decreased lysosomal acidity, resulting in reduced TLR9 activation, thereby impairing viral DNA sensing and IFN-I production. Lapf deficiency also reduced lysosomal membrane stability, facilitating the escape of HSV-1 DNA into the cytoplasm, where it could amplify and reactivate. Conversely, Lapf overexpression enhanced lysosomal acidity and membrane stability, promoting TLR9 activation and antiviral innate immunity. Furthermore, Lapf deficiency markedly reduced the phosphorylation of STING, TBK1, and IRF3, whereas Lapf overexpression restored cGAS-STING signaling. This effect was abolished by lysosomal acidification inhibitor chloroquine (CQ), supporting that LAPF promotes lysosomal acidification-dependent antiviral immunity via TLR9 and cGAS-STING pathways. Pharmacological enhancement of LAPF activity using the dephosphorylation inhibitor SHP099 alleviated neuroinflammation and mechanical allodynia in HSV-1-induced neuroinflammatory pain model mice, suggesting potential therapeutic implications. In conclusion, our findings demonstrate that LAPF enhances lysosomal acidification to promote dual antiviral innate immune responses via TLR9 and cGAS-STING pathways in HSV-1 infection, thereby attenuating HSV-1-induced neuroinflammatory pain. These results provide mechanistic insights and potential therapeutic targets for virus-associated neuroinflammatory pain.