Detection of microbial DNA is a primary means of host defense. In mammalian cells, DNA-sensing pathways induce robust anti-microbial responses and initiation of adaptive immunity, leading to the eventual clearance of the infectious agent. However, while conferring the advantage of broad detection capability, the sequence-independent recognition mechanisms of most DNA sensors pose a significant challenge for mammalian cells to maintain ignorance to self-DNA under homeostatic conditions. In this Review, we summarize the fundamentals of DNA-sensing pathways and the intricate regulatory networks that keep these pathways in check. In addition, we describe how regulatory restraints can be defective and underlie human autoinflammatory and autoimmune diseases. Further, we discuss therapies in development that limit inflammation fueled by self-DNA or inappropriate activation of DNA-sensing pathways.

检测微生物 DNA 是宿主防御的主要手段。在哺乳动物细胞中，DNA 感应通路诱导强大的抗微生物反应和适应性免疫的启动，导致感染源最终清除。然而，虽然赋予了广泛的检测能力的优势，但大多数 DNA 传感器的序列非依赖性识别机制对哺乳动物细胞在稳态条件下保持对自身 DNA 的无知构成了重大挑战。在这篇综述中，我们总结了 DNA 感应通路的基本原理以及控制这些通路的复杂调控网络。此外，我们还描述了调节限制如何存在缺陷并成为人类自身炎症和自身免疫性疾病的基础。此外，我们讨论了正在开发的疗法，这些疗法限制了由自身 DNA 或 DNA 感应通路的不当激活引起的炎症。