Abstract
Aicardi–Goutières syndrome (AGS) is a rare early onset childhood encephalopathy caused by persistent neuroinflammation of autoimmune origin. AGS is a genetic disorder and >50% of affected individuals bear hypomorphic mutations in ribonuclease H2 (RNase H2). All available RNase H2 mouse models so far fail to mimic the prominent CNS involvement seen in AGS. To establish a mouse model recapitulating the human disease, we deleted RNase H2 specifically in the brain, the most severely affected organ in AGS. Although RNase H2ΔGFAP mice lacked the nuclease in astrocytes and a majority of neurons, no disease signs were apparent in these animals. We additionally confirmed these results in a second, neuron-specific RNase H2 knockout mouse line. However, when astrocytes were isolated from brains of RNase H2ΔGFAP mice and cultured under mitogenic conditions, they showed signs of DNA damage and premature senescence. Enhanced expression of interferon-stimulated genes (ISGs) represents the most reliable AGS biomarker. Importantly, primary RNase H2ΔGFAP astrocytes displayed significantly increased ISG transcript levels, which we failed to detect in in vivo in brains of RNase H2ΔGFAP mice. Isolated astrocytes primed by DNA damage, including RNase H2-deficiency, exhibited a heightened innate immune response when exposed to bacterial or viral antigens. Taken together, we established a valid cellular AGS model that utilizes the very cell type responsible for disease pathology, the astrocyte, and phenocopies major molecular defects observed in AGS patient cells.
Highlights
Aicardi–Goutières syndrome (AGS) is an inherited autoimmune disorder typically affecting the brain and, to a lesser extent, the skin
High expression was observed in the subgranular zone (SGZ) of the hippocampal dentate gyrus, a region typically associated with adult hippocampal neurogenesis and proliferation
AGS is of genetic origin and mainly affects the brain, extraneurological symptoms such as chilblain lesions of the skin are frequent [2]
Summary
Aicardi–Goutières syndrome (AGS) is an inherited autoimmune disorder typically affecting the brain and, to a lesser extent, the skin. Two hypomorphic RNase H2 mouse models have been generated recently and depending on the introduced patient mutation, the animals die perinatally (G37S mutation in the catalytic A subunit) or display no overt phenotype (A177T mutation in the accessory B subunit) [16, 17]. Both mouse models exhibit ISG upregulation in some tissues, no signs of neuroinflammation were apparent. We believe that the RNase H2-deficient astrocytes generated in this study can serve as a valid cellular model for AGS, especially as they represent the very cell type considered to govern the pathogenic interferon α expression in human patients
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