Enhanced inflammatory signaling driven by metabolic switch in Aicardi-Goutieres syndrome
Batignes, M.; Luka, M.; Jagtap, S.; de Cevins, C.; Nemazanyy, I.; Fali, T.; Garcia-Paredes, V.; Carbone, F.; Perot, B. P.; Neven, B.; Bader-Meunier, B.; Quartier dit Maire, P.; Hully, M.; Belot, A.; Lepelley, A.; Fremond, M.-L.; Crow, Y. J.; Fischer, A.; Menager, M. M.
Show abstract
Aicardi-Goutieres syndrome (AGS) is a genetic type I interferon (IFN)-mediated disease characterised by neurological involvement with onset in childhood. Chronic inflammation in response to uncontrolled type I IFN production is, among other things, associated with IP-10 secretion. We analysed, at the single-cell transcriptomic levels, peripheral blood samples from patients bearing AGS-causing mutations in SAMHD1, RNASEH2B or ADAR1 genes. Using machine-learning approaches and differential gene expression we identified a drastic loss of transcription factor hypoxia induced factor 1 (HIF-1) expression and activity associated with features of a metabolic switch and mitochondrial stress in monocytes/dendritic cells. Chemical stabilization of HIF-1, with a synthetic drug in an in vitro model of AGS, allowed us to reverse the energy metabolic switch, attenuate mitochondrial stress and markedly reduce IP-10 production. We therefore propose that energy metabolic switch contributes to exacerbated chronic inflammation in AGS, and that targeting this pathway might represent a promising therapeutic approach.
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