Aicardi Goutières Syndrome (AGS)
https://elifesciences.org/articles/102900
Microglia are the resident immune cells of the brain and spinal cord. They play essential roles in brain development, maintenance, and responses to injury or disease. However, studying microglia in the laboratory is difficult because they rapidly lose their identity outside the brain and are challenging to genetically manipulate. This makes it harder to investigate how microglia contribute to neurological diseases and to develop targeted therapies. One promising strategy is microglia replacement, where other immune cells are transplanted into the brain to take on microglia-like roles. In this study, the researchers introduced a new tool for microglia replacement using oestrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalised macrophages. These cells are generated from mouse bone marrow and can be expanded indefinitely in the laboratory before being differentiated into macrophages. They found that ER-Hoxb8 macrophages closely resemble primary bone marrow–derived macrophages in their structure, gene expression, and immune functions. When transplanted into brains lacking microglia, they successfully engrafted into brain tissue and adopted many key features of microglia, becoming microglia-like cells. The researchers then used this system to investigate Aicardi–Goutières syndrome (AGS), a rare inherited interferonopathy that primarily affects the brain and immune system. AGS can be caused by mutations in ADAR1, a gene involved in RNA editing and regulation of immune responses. Using CRISPR–Cas9 gene editing, they created ER-Hoxb8 cells carrying ADAR1 mutations. These mutations triggered strong type I interferon responses and impaired macrophage development. Importantly, microglia-like cells carrying a patient-derived ADAR1 mutation induced interferon-stimulated gene activity in the brain after transplantation. These findings suggest that dysfunctional microglia can directly drive brain inflammation in AGS and demonstrate the value of ER-Hoxb8 cells as a powerful model for studying microglia in neurological disease.