Genomic instability is a key driving force for the development and progression of many age-related neurodegenerative diseases and central nervous system (CNS) cancers. Recently, the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), has been shown to detect and respond to self-DNA accumulation resulting from DNA damaging insults in peripheral cell types. cGAS has been shown to be important in the responses of microglia to DNA viruses and amyloid beta, and we have reported that it underlies the responses of human microglia to exogenous DNA. However, the role of this cytosolic sensor in the detection of self-DNA by glia is poorly understood and its ability to mediate the cellular responses of human microglia to genotoxic DNA damage has not been established. Here, we describe the ability of ionizing radiation and oxidative stress to elicit genomic DNA damage in human microglial cells and to stimulate the production of key inflammatory mediators by these cells in an NF-kB dependent manner. Importantly, we have utilized CRISPR/Cas9 and siRNA-mediated knockdown approaches and a pharmacological inhibitor of the cGAS adaptor protein stimulator of interferon genes (STING) to demonstrate that the cGAS-STING pathway plays a critical role in the generation of these microglial immune responses to such genotoxic insults. Together, these studies support the notion that cGAS mediates the detection of cytosolic self-DNA by microglia, providing a potential mechanism linking genomic instability to the development of CNS cancers and neurodegenerative disorders.

基因组不稳定性是许多与年龄相关的神经退行性疾病和中枢神经系统（CNS）癌症发生和进展的关键驱动力。最近，胞质 DNA 传感器，环 GMP-AMP 合酶 (cGAS)，已被证明可以检测和响应外周细胞类型中 DNA 损伤性损伤引起的自身 DNA 积累。cGAS 已被证明在小胶质细胞对 DNA 病毒和淀粉样蛋白 β 的反应中发挥重要作用，我们报道它是人类小胶质细胞对外源 DNA 反应的基础。然而，人们对这种胞质传感器在神经胶质细胞检测自身DNA中的作用知之甚少，并且其介导人类小胶质细胞对基因毒性DNA损伤的细胞反应的能力尚未确定。在这里，我们描述了电离辐射和氧化应激引起人类小胶质细胞基因组 DNA 损伤并以 NF-kB 依赖性方式刺激这些细胞产生关键炎症介质的能力。重要的是，我们利用 CRISPR/Cas9 和 siRNA 介导的敲除方法以及干扰素基因 cGAS 接头蛋白刺激物 (STING) 的药理学抑制剂来证明 cGAS-STING 通路在这些小胶质细胞免疫反应的产生中发挥着关键作用对于这种基因毒性的侮辱。总之，这些研究支持了 cGAS 介导小胶质细胞对胞质自身 DNA 的检测的观点，提供了将基因组不稳定性与中枢神经系统癌症和神经退行性疾病的发展联系起来的潜在机制。