Restoration of Proteostasis in the Endoplasmic Reticulum Reverses an Inflammation-Like Response to Cytoplasmic DNA inCaenorhabditis elegans

Abstract

Caenorhabditis elegans possesses a rudimentary innate immune response that serves as a model for various aspects of the human innate immune response. To date, a nematode response to pathogenic cytoplasmic DNA has not been identified... Innate immune responses protect organisms against various insults, but may lead to tissue damage when aberrantly activated. In higher organisms, cytoplasmic DNA can trigger inflammatory responses that can lead to tissue degeneration. Simpler metazoan models could shed new mechanistic light on how inflammatory responses to cytoplasmic DNA lead to pathologies. Here, we show that in a DNase II-defective Caenorhabditis elegans strain, persistent cytoplasmic DNA leads to systemic tissue degeneration and loss of tissue functionality due to impaired proteostasis. These pathological outcomes can be therapeutically alleviated by restoring protein homeostasis, either via ectopic induction of the ER unfolded protein response or N-acetylglucosamine treatment. Our results establish C. elegans as an ancestral metazoan model for studying the outcomes of inflammation-like conditions caused by persistent cytoplasmic DNA and provide insight into potential therapies for human conditions involving chronic inflammation.

Self-DNA Exposure Induces Developmental Defects and Germline DNA Damage Response in Caenorhabditis elegans

“…Here, we investigated the effects of self-DNA exposure in C. elegans . This organism has been widely used as an infection model to study how it responds to and how it recognises PAMPs [ 39 , 40 ], but only very recently, it was explored as a model to study the effects of non-self cytoplasmic DNA [ 41 ]. In our experiments, the effects of self-DNA exposure, mediated by a diet based on bacteria bearing a C. elegans genomic library, were compared to the effects of a control diet based on bacteria bearing an M. truncatula genomic library.…”

“…Cytoplasmic DNA-sensors have not been discovered in C. elegans , but it has been recently demonstrated that persistent, E. coli derived, cytoplasmic DNA leads to detrimental effects and loss of functionality in the analysed tissues [ 41 ]. These authors found that all the observed tissue degeneration phenotypes were fully alleviated by loss of FSHR-1, a G protein-coupled receptor required for the activation of infection and stress response genes [ 44 ].…”

An integrated view of innate immune mechanisms in C. elegans

“…The IPR is an example of a surveillance mechanism, set-off by so-called 'homeostasis-altering molecular processes' (HAMPs) (35), rather than microbeassociated molecular patterns (MAMPs) such as lipopolysaccharide and peptidoglycan, or damage-associated molecular patterns (DAMPs), cellular components released inappropriately, including extra-cellular ATP, and mitochondrial DNA in the cytoplasm. A slew of other surveillance mechanisms have now been described in C. elegans, involving for example, the monitoring of cytoplasmic DNA (36), translation, and mitochondrial function (reviewed in (37,38)). Interestingly, the RNA interference (RNAi) machinery that, in conjunction with 3' uridylation of the viral genomic RNA (39), is central to anti-viral defence in C. elegans (40), appears to target mRNA during active translation (41), suggesting potential cross-talk between RNAi and translation surveillance.…”