MDA5 is a cytoplasmic double-stranded RNA sensor that triggers type I interferon (IFN-I) production. The gain-of-function mutations in MDA5 cause Aicardi-Goutières syndrome (AGS), a genetic disorder characterized by an infancy-onset inflammatory encephalopathy. AGS is also caused by mutations in six other genes affecting nucleotide metabolism: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, ADAR1, and SAMHD1. However, mice deficient in these genes were reported not to develop obvious encephalitis.
Here we revealed spontaneous encephalitis in mutant mice with gain-of-function mutations of MDA5 generated by ENU mutagenesis, which were previously reported to develop lupus-like autoimmune symptoms. FDG-PET analysis showed a MAVS-dependent high accumulation in the kidney and brain, suggesting severe inflammation in the both organs. The mice displayed upregulation of IFN-I in the brain with no infiltration of lymphocytes and microglia were the major source. Through histological and flow cytometric analysis, enrichment of astrocytes and microglia, which is called astrocytosis and microgliosis respectively, was observed in the whole brain in both MAVS and IFN-I dependent manner. Although multiple autoantibodies were detected in the sera of the mice and also AGS patients, the mutant mice intercrossed with Rag2 deficient mice also exhibited upregulation of IFN-I, astrocytosis and microgliosis, indicating autoantibodies or lymphocytes did not contribute to development of the encephalitis. Furthermore, microglia in mutant mice were in an activated status with high CD45 expression, less production of neurotrophic factors and enhanced phagocytic capability. These data suggested that not only IFN-I but also microgliosis was involved in the pathogenesis of this encephalitis. Although there was no detectable calcification, IFN-I upregulation in the absence of lymphocyte infiltration is a common feature with human AGS. Taken together, these mice have the potential to be used for exploiting clinical treatments of AGS. Moreover, we would like to propose that microglia can be one of targets for AGS therapy.