Enhanced inflammatory signaling driven by metabolic switch in Aicardi-Goutières syndrome

Abstract

SummaryAicardi-Goutières 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 inSAMHD1,RNASEH2BorADAR1genes. Using machine-learning approaches and differential gene expression we identified a drastic loss of transcription factor hypoxia induced factor 1 α (HIF-1α) expression and activity associated with features of a metabolic switch and mitochondrial stress in monocytes/dendritic cells. Chemical stabilization of HIF-1α, with a synthetic drug in anin vitromodel 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.