生物
小胶质细胞
基因组不稳定性
细胞生物学
DNA损伤
趋化性
趋化因子
神经炎症
炎症
免疫学
遗传学
DNA
受体
作者
Emily Talbot,Lisha Joshi,Peter Thornton,Mahya Dezfouli,Kalliopi Tsafou,Michael S. Perkinton,S. V. Khoronenkova
摘要
Abstract Defective DNA damage signalling and repair is a hallmark of age-related and genetic neurodegenerative disease. One mechanism implicated in disease progression is DNA damage-driven neuroinflammation, which is largely mediated by tissue-resident immune cells, microglia. Here, we utilise human microglia-like cell models of persistent DNA damage and ATM kinase deficiency to investigate how genome instability shapes microglial function. We demonstrate that upon DNA damage the cytosolic DNA sensing cGAS-STING axis drives chronic inflammation and a robust chemokine response, exemplified by production of CCL5 and CXCL10. Transcriptomic analyses revealed that cell migratory pathways were highly enriched upon IFN-β treatment of human iPSC-derived microglia, indicating that the chemokine response to DNA damage mirrors type I interferon signalling. Furthermore, we find that STING deletion leads to a defect in microglial chemotaxis under basal conditions and upon ATM kinase loss. Overall, this work provides mechanistic insights into cGAS-STING-dependent neuroinflammatory mechanisms and consequences of genome instability in the central nervous system.
科研通智能强力驱动
Strongly Powered by AbleSci AI