DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity
DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity
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DOI：
10.1016/j.immuni.2015.01.012
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发表时间：
2015-02-17
期刊：
影响因子：
32.4
通讯作者：
Gekara, Nelson O.
中科院分区：
文献类型：
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作者：
Hartlova, Anetta;Erttmann, Saskia F.;Gekara, Nelson O.
共济失调-毛细血管扩张突变（ATM）是DNA修复机制的核心组成部分，其功能障碍导致共济失调毛细血管扩张（AT），这是一种具有多种炎症表现的癌症易感性疾病。通过分析AT患者样本和Atm（-/-）小鼠，我们发现未修复的DNA损伤诱导I型干扰素（IFN），导致Atm（-/-）小鼠的抗病毒和抗细菌反应增强。通过DNA损伤引发I型干扰素系统涉及将DNA释放到细胞质中，在细胞质中其激活胞质DNA传感STING介导的途径，这进而通过激活Toll样受体、RIG-I样受体、细胞质DNA传感器及其下游信号传导伴侣的表达来增强对先天性刺激的应答。这项研究为AT患者的炎性表型提供了一个潜在的解释，并将受损的DNA确定为细胞内在的危险信号，该信号可引发先天免疫系统对微生物和环境威胁的快速和放大反应。
Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.