Activation of the endoplasmic reticulum unfolded protein response reverses an inflammation-like response to cytoplasmic DNA

Innate immune responses protect organisms against various insults, but may lead to tissue damage when aberrantly activated. In higher organisms, cytoplasmic DNA can trigger inflammation that can lead to tissue degeneration. Simpler in vivo models could shed new mechanistic light on how inflammatory responses to cytoplasmic DNA lead to pathology. Here we show that in DNase II-deficient Caenorhabditis elegans, persistent foreign cytoplasmic DNA leads to systemic tissue degeneration, and we identify impaired protein homeostasis as an inflammatory pathomechanism. This pathological outcome can be alleviated by improving protein homeostasis, either via ectopic induction of the endoplasmic reticulum unfolded protein response (UPRER) or by treatment with N-acetylglucosamine. Our results establish C. elegans as an ancestral metazoan model for studying outcomes of inflammation-like conditions caused by persistent cytoplasmic DNA and provide insight into potential therapies for conditions involving chronic inflammation.