Aberrant multicellular interferon signaling underlies Adar1 mutation-driven Aicardi-Goutières syndrome-like...

Adenosine-to-inosine RNA editing by ADAR1 prevents aberrant innate immunity activation by modifying endogenous double-stranded RNA. Mice carrying a left-handed double-stranded RNA (Z-RNA) binding-deficient mutation develop Aicardi-Goutières syndrome (AGS)-like encephalopathy, characterized by ventricular enlargement, gliosis, calcification, and white matter degeneration with a type I interferon (IFN) signature. However, the mechanisms underlying encephalopathy development remain unknown. Here, we show that pathology was most severe in periventricular regions where IFN-stimulated gene (ISG) expression was elevated and ependymal cells were lost, accompanied by higher IFN-α levels in cerebrospinal fluid than in sera. Blocking type I IFN signaling fully reversed these abnormalities, which was not achieved by deleting downstream PKR or ZBP1. Microglial elimination partially alleviated the encephalopathy without suppressing ISGs. In contrast, neuron- or astrocyte-specific ADAR1 dysfunction evoked robust ISG expression and recapitulated AGS-like encephalopathy, with astrocytic dysfunction causing particularly severe effects. These findings identify aberrant multicellular IFN signaling as the central driver of AGS-like encephalopathy.