Microglial specific ADAR1 mutation exhibits different innate immune activation from ADAR1 gene deletion in the brain 4044

Abstract Description Microglial specific ADAR1 mutation exhibits different innate immune activation from ADAR1 gene deletion in the brain Xinfeng Guo, Chaowei Shang, Clayton Wiley, Richard A. Steinman, Timothy R. Billiar and Qingde Wang Microglial cells, the brain’s resident macrophages, are believed to play a central role in driving Aicardi-Goutières Syndrome (AGS) development. Microglial activation caused by an AGS mutation may influence other brain cells, leading to neuroinflammatory damage. However, directly testing this hypothesis in an animal model has been challenging due to technical barriers in limiting a genetic mutation to a specific cell type. The ADAR1 P193A mutation is the most common mutation in type six AGS. To investigate its role in microglial cells, we developed a mouse model in which the P193A mutation exerts its effects exclusively in microglial cells. Using specific genotyping and brain morphological studies, including RNA in situ hybridization and pathological analysis, we confirmed that the P193A mutation was present solely in microglial cells. We assessed the inflammatory status in this model and compared it with a microglial-specific ADAR1 KO model. Interestingly, the microglia-specific P193A mutation exhibited a distinct innate immune activation pattern compared to ADAR1 deletion. This study not only provides insights into the microglia of ADAR1 P193A mutation but also introduces a method that could be applied to investigate other genetic mutations in specific cell types. Funding Sources Supported by NIH AI139544, NS134651 and NS138573 Topic Categories Neuroimmunology (NEUR)