Self-DNA sensing by the immune system has emerged as a key contributing response in the pathogenesis of cancer and autoimmune diseases. Recent studies have established that release of nuclear and mitochondrial DNA can also drive lung inflammatory diseases. Here, we review the latest advances on self-DNA sensing and signaling, the influence of these pathways on lung inflammation, and how these findings contribute to our understanding of basic mechanisms of innate immunity. Within a dozen DNA sensors, the cGAS/STING, inflammasomes and Toll-Like Receptor pathways are central to nucleic acid sensing. We propose a key role for the STING pathway in self-DNA sensing in inflammatory lung conditions, and identify major remaining questions that may further our understanding and potential to control self-DNA sensing and innate immune activation.
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