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

Abstract

The livers of DNase II–deficient mouse embryos contain many macrophages carrying undigested DNA, and the embryos die in utero. Here we report that erythroid precursor cells underwent apoptosis in the livers of DNase II–deficient embryos and that in the liver, interferon-β mRNA was expressed by the resident macrophages. When the DNase II–deficient mice were crossed with mice deficient in type I interferon receptor, the resultant 'double-mutant' mice were born healthy. The double-mutant embryos expressed interferon-β mRNA, but the expression of a subset of the interferon-responsive genes dysregulated in DNase II–deficient embryos was restored to normal. These results indicate that the inability to degrade DNA derived from erythroid precursors results in interferon-β production that induces expression of a specific set of interferon-responsive genes associated with embryonic lethality in DNase II–deficient mice.

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Figure 1: Apoptotic cell death of fetal liver cells in Dnase2a−/− embryos.
Figure 2: Induction of interferon genes in the fetal liver of Dnase2a−/− mice.
Figure 3: Identification of interferon-producing cells in Dnase2a−/− fetal liver.
Figure 4: 'Rescue' of the embryonic lethality of DNase II deficiency by deficiency in IFN-β signaling.
Figure 5: Expression of interferon genes in Dnase2a−/−Ifnar1−/− fetal liver.

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Acknowledgements

We thank K. Miwa for genotyping the mice; and M. Fujii and M. Harayama for secretarial assistance. Supported by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture in Japan.

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Correspondence to Shigekazu Nagata.

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The authors declare no competing financial interests.

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Yoshida, H., Okabe, Y., Kawane, K. et al. Lethal anemia caused by interferon-β produced in mouse embryos carrying undigested DNA. Nat Immunol 6, 49–56 (2005). https://doi.org/10.1038/ni1146

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