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

Aicardi-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 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 alpha (HIF-1a) expression and activity associated with features of a metabolic switch and mitochondrial stress in monocytes/dendritic cells. Chemical stabilization of HIF-1a, 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. ### Competing Interest Statement M.M.M. and M.B. are listed as inventors on a patent application related to this article (European Patent Application no.EP23305153.1, entitled Use of HIF-1 stabilizing agents for the treatment of type I interferonopathies).