HSV-1 reactivation results in post-herpetic neuralgia by upregulating Prmt6 and inhibiting cGAS-STING

Brain. 2024 Jul 5;147(7):2552-2565. doi: 10.1093/brain/awae053.

Abstract

Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of post-herpetic neuralgia (PHN). The immune escape mechanism of VZV remains elusive. As 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 the cGAS-STING pathway, providing novel insights and a potential therapeutic target for PHN.

Keywords: Prmt6; antiviral innate immunity; cGAS-STING; microglia; post-herpetic neuralgia.

MeSH terms

  • Animals
  • Herpes Simplex / immunology
  • Herpesvirus 1, Human*
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Male
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / immunology
  • Microglia / metabolism
  • Neuralgia, Postherpetic* / immunology
  • Neuralgia, Postherpetic* / metabolism
  • Nucleotidyltransferases* / genetics
  • Nucleotidyltransferases* / metabolism
  • Protein Serine-Threonine Kinases
  • Protein-Arginine N-Methyltransferases* / antagonists & inhibitors
  • Protein-Arginine N-Methyltransferases* / genetics
  • Protein-Arginine N-Methyltransferases* / metabolism
  • Up-Regulation*

Substances

  • Protein-Arginine N-Methyltransferases
  • Membrane Proteins
  • Nucleotidyltransferases
  • cGAS protein, mouse
  • Sting1 protein, mouse
  • PRMT6 protein, mouse
  • Tbk1 protein, mouse
  • Interferon Regulatory Factor-3
  • Protein Serine-Threonine Kinases