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<p>Aicardi-Goutières syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterized by neurological involvement with onset <i>in utero</i> or in childhood. Here, we analyze peripheral blood samples from patients bearing AGS-causing mutations in <i>ADAR1, RNASEH2B</i> or <i>SAMHD1</i> using single-cell transcriptomics and targeted metabolomics. Using machine-learning approaches and differential gene expression analysis, we identified a loss of transcription factor hypoxia induced factor 1 α (HIF-1α) expression and activity associated with features of a metabolic switch favoring oxidative phosphorylation and glutathione metabolism over glycolysis in monocytes and dendritic cells. Evidences of mitochondrial stress and accumulation of cytosolic double-stranded DNA and RNA were also found. The energy metabolic switch was confirmed at the metabolic level in primary peripheral blood mononuclear cells of AGS patients. Chemical stabilization of HIF-1α using a synthetic drug in in vitro cellular models of AGS, reversed the energy metabolic switch towards glycolysis, attenuated mitochondrial stress, and markedly reduced the IFN response and IP-10 production. We therefore propose that an energy metabolic switch contributes to chronic inflammation in AGS and that targeting this pathway might represent a potential therapeutic approach.</p>

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Pharmacological stabilization of hypoxia-inducible factor 1-α dampens the interferon response and promotes glycolysis in Aicardi-Goutières syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月3日

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  • Maxime Batignes,
  • Marine Luka,
  • Surabhi Jagtap,
  • Camille de Cevins,
  • Ivan Nemazanyy,
  • Jacqueline Leib,
  • Tinhinane Fali,
  • Alexandre Pierga,
  • Mohammed Zarhrate,
  • Víctor García-Paredes,
  • Francesco Carbone,
  • Brieuc P. Pérot,
  • Bénédicte Neven,
  • Brigitte Bader-Meunier,
  • Pierre Quartier,
  • Marie Hully,
  • Alexandre Belot,
  • Alice Lepelley,
  • Marie-Louise Frémond,
  • Alain Fischer,
  • Mickaël M. Ménager

摘要

Aicardi-Goutières syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterized by neurological involvement with onset in utero or in childhood. Here, we analyze peripheral blood samples from patients bearing AGS-causing mutations in ADAR1, RNASEH2B or SAMHD1 using single-cell transcriptomics and targeted metabolomics. Using machine-learning approaches and differential gene expression analysis, we identified a loss of transcription factor hypoxia induced factor 1 α (HIF-1α) expression and activity associated with features of a metabolic switch favoring oxidative phosphorylation and glutathione metabolism over glycolysis in monocytes and dendritic cells. Evidences of mitochondrial stress and accumulation of cytosolic double-stranded DNA and RNA were also found. The energy metabolic switch was confirmed at the metabolic level in primary peripheral blood mononuclear cells of AGS patients. Chemical stabilization of HIF-1α using a synthetic drug in in vitro cellular models of AGS, reversed the energy metabolic switch towards glycolysis, attenuated mitochondrial stress, and markedly reduced the IFN response and IP-10 production. We therefore propose that an energy metabolic switch contributes to chronic inflammation in AGS and that targeting this pathway might represent a potential therapeutic approach.