Lethal anemia caused by interferon-β produced in mouse embryos carrying undigested DNA

Yoshida, Hideyuki; Okabe, Yasutaka; Kawane, Kohki; Fukuyama, Hidehiro; Nagata, Shinji

doi:10.1038/ni1146

Cited by 333 publications

(295 citation statements)

References 41 publications

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“…Mice lacking DNase II show a dramatic STING-dependent type I IFN response because of the fact that DNA within the lysosomal compartment of phagocytic cells fails to be degraded and subsequently translocates into the cytoplasm (23). It appears likely that cGAS also plays a pivotal role in this disease setting, yet additional proof is required to substantiate this assumption.…”

Section: Discussionmentioning

confidence: 98%

TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner

Ablasser

Hemmerling

Schmid-Burgk

et al. 2014

The Journal of Immunology

219

158

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Cytosolic detection of DNA is crucial for the initiation of antiviral immunity but can also cause autoimmunity in the context of endogenous nucleic acids being sensed. Mutations in the human 3′ repair exonuclease 1 (TREX1) have been linked to the type I IFN–associated autoimmune disease Aicardi–Goutières syndrome. The exact mechanisms driving unabated type I IFN responses in the absence of TREX1 are only partly understood, but it appears likely that accumulation of endogenous DNA species triggers a cell-autonomous immune response by activating a cytosolic DNA receptor. In this article, we demonstrate that knocking out the DNA sensor cyclic GMP–AMP synthase completely abrogates spontaneous induction of IFN-stimulated genes in TREX1-deficient cells. These findings indicate a key role of cyclic GMP–AMP synthase for the initiation of self-DNA–induced autoimmune disorders, thus providing important implications for novel therapeutic approaches.

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Section: Discussionmentioning

confidence: 98%

TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner

Ablasser

Hemmerling

Schmid-Burgk

et al. 2014

The Journal of Immunology

219

158

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show abstract

“…Although an increase in antimicrobial peptide production would be expected to partially compensate for the loss of hemocyte function, this was clearly not the case. This perplexing result is reminiscent of the embryonic lethality observed in dnase II-knockout mice which is caused by an unexpected overexpression of INF-β by macrophages [10][11][12]. Apart from antimicrobial peptide induction, it has been demonstrated that dDNase II itself is significantly induced by bacterial and fungal infection [41,42].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, targeted mutation of the dnase II gene in the germline of mice resulted in perinatal lethality presumably due to loss definitive erythropoiesis [9,10]. Subsequent analyses of these mutant mice revealed that dnase II-deficient macrophages accumulate ingested DNA and overexpress β-interferon (INFβ) resulting in embryonic lethality [11,12].…”

Section: Introductionmentioning

confidence: 99%

DNase II deficiency impairs innate immune function in Drosophila

Seong

Varela-Ramı́rez

Aguilera

2006

Cellular Immunology

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DNase II enzymes are highly conserved proteins that are required for the degradation of DNA within phagolysosomes. Engulfment of apoptotic cells and/or bacteria by phagocytic cells requires the function of DNase II to completely destroy ingested DNA. Mutation of the dnase II gene results in an increase of undegraded apoptotic DNA within phagocytic cells in mice and nematodes. Additionally, reduction of DNase II enzymatic activity in Drosophila melanogaster has been shown to lead to increased accumulation of DNA in the ovaries. Due to the importance of DNA clearance during infection, we hypothesized that a severe reduction of DNase II activity would result in diminished immune function and viability. To test this hypothesis, we knocked down DNase II activity in flies using RNAi. As expected, expression of a dnase II-RNAi construct in flies resulted in a dramatic reduction of DNase II activity and a significant decrease in total hemocyte numbers. Furthermore, infection of dnase II-RNAi flies with Gram negative or positive bacteria resulted in a severe reduction in fly viability. These results confirm that DNase II and the ability to clear macromolecular DNA is essential for maintaining proper immune function in Drosophila.

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“…Under certain conditions, self DNA is inappropriately delivered to the cytosol, resulting in autoimmune responses. For example, DNase II-deficient macrophages lack the ability to digest self-DNA from engulfed apoptotic cells, leading to IFN-β production Yoshida et al, 2005). However, the mechanism by which cytosolic DNA induces IFNs is not well understood.…”

Section: Introductionmentioning

confidence: 99%

RNA Polymerase III Detects Cytosolic DNA and Induces Type I Interferons through the RIG-I Pathway

Chiu¹,

MacMillan²,

Chen³

2009

Journal of End-to-End-testing

195

255

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SummaryType-I interferons (IFNs) are important for antiviral and autoimmune responses. Retinoic acidinduced gene I (RIG-I) and mitochondrial antiviral signaling (MAVS) proteins mediate IFN production in response to cytosolic double-stranded RNA or single-stranded RNA containing 5′-triphosphate (5′-ppp). Cytosolic B-form double-stranded DNA, such as poly(dA-dT)·poly(dA-dT) [poly(dA-dT)], can also induce IFN-β, but the underlying mechanism is unknown. Here we show that the cytosolic poly(dA-dT) DNA is converted into 5′-ppp RNA to induce IFN-β through the RIG-I pathway. Biochemical purification led to the identification of DNA-dependent RNA polymerase III (Pol-III) as the enzyme responsible for synthesizing 5′-ppp RNA from the poly(dA-dT) template. Inhibition of RNA Pol-III prevents IFN-β induction by transfection of DNA or infection with DNA viruses. Furthermore, Pol-III inhibition abrogates IFN-β induction by the intracellular bacterium Legionella pneumophila and promotes the bacterial growth. These results suggest that RNA Pol-III is a cytosolic DNA sensor involved in innate immune responses.

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Lethal anemia caused by interferon-β produced in mouse embryos carrying undigested DNA

Cited by 333 publications

References 41 publications

TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner

TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner

DNase II deficiency impairs innate immune function in Drosophila

RNA Polymerase III Detects Cytosolic DNA and Induces Type I Interferons through the RIG-I Pathway

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