Brain aging and neurodegeneration are associated with prominent microglial reactivity and activation of innate immune response pathways, commonly referred to as neuroinflammation. One such pathway, the type I interferon response, recognizes viral or mitochondrial DNA in the cytoplasm via activation of the recently discovered cyclic dinucleotide synthetase cGAS and the cyclic dinucleotide receptor STING. Here we show that the FDA-approved antiviral drug ganciclovir (GCV) induces a type I interferon response independent of its canonical thymidine kinase target. Inhibition of components of the STING pathway, including STING, IRF3, Tbk1, extracellular IFNβ, and the Jak-Stat pathway resulted in reduced activity of GCV and its derivatives. Importantly, functional STING was necessary for GCV to inhibit inflammation in cultured myeloid cells and in a mouse model of multiple sclerosis. Collectively, our findings uncover an unexpected new activity of GCV and identify the STING pathway as a regulator of microglial reactivity and neuroinflammation.

中文翻译：

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STING依赖的I型干扰素反应的激活减少了小胶质细胞反应性和神经炎症。

脑衰老和神经退行性变与显着的小胶质细胞反应性和先天性免疫反应途径（通常称为神经发炎）的激活有关。一种这样的途径，即I型干扰素应答，通过激活最近发现的环状二核苷酸合成酶cGAS和环状二核苷酸受体STING来识别细胞质中的病毒或线粒体DNA。在这里，我们显示了FDA批准的抗病毒药物更昔洛韦（GCV）诱导I型干扰素反应，独立于其典型的胸苷激酶靶标。抑制STING途径的成分，包括STING，IRF3，Tbk1，细胞外IFNβ和Jak-Stat途径，导致GCV及其衍生物的活性降低。重要的，功能性STING对于GCV抑制培养的髓样细胞和多发性硬化症小鼠模型中的炎症是必需的。总的来说，我们的发现揭示了GCV意外的新活性，并确定STING通路是小胶质细胞反应性和神经炎症的调节剂。