Microglial double stranded DNA accumulation induced by DNase II deficiency drives neuroinflammation and neurodegeneration

作者：Lingjie Li, Shiyu Liang, Xiaoying Sun, Jie Zhu, Xiao-yun Niu, Xiaoyu Du, Yaru Huang, Rui‐tian Liu · 发表于：Journal of Neuroinflammation · 年份：2025 · DOI：10.1186/s12974-025-03333-6 · 被引用次数：12 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、interferon and immune responses、Inflammasome and immune disorders

BACKGROUND: Deoxyribonuclease 2 (DNase II) is pivotal in the clearance of cytoplasmic double stranded DNA (dsDNA). Its deficiency incurs DNA accumulation in cytoplasm, which is a hallmark of multiple neurodegenerative diseases. Our previous study showed that neuronal DNase II deficiency drove tau hyperphosphorylation and neurodegeneration (Li et al., Transl Neurodegener 13:39, 2024). Although it has been verified that DNase II participates in type I interferons (IFN-I) mediated autoinflammation and senescence in peripheral systems, the role of microglial DNase II in neuroinflammation and neurodegenerative diseases such as Alzheimer's disease (AD) is still unknown. METHODS: The levels of microglial DNase II in triple transgenic AD mice (3xTg-AD) were measured by immunohistochemistry. The cognitive performance of microglial DNase II deficient WT and AD mice was determined using the Morris water maze test, Y-maze test, novel object recognition test and open filed test. To investigate the impact of microglial DNase II deficiency on microglial morphology, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and IFN-I pathway, neuroinflammation, synapses loss, amyloid pathology and tauopathy, the levels of cGAS-STING and IFN-I pathway related protein, gliosis and proinflammatory cytokines, synaptic protein, complement protein, Aβ levels, phosphorylated tau in the brains of the microglial DNase II deficient WT and AD mice were evaluated by immunolabeling, im...