A large amount of chromosomal DNA is degraded during programmed cell death and definitive erythropoiesis1. DNase II is an enzyme that digests the chromosomal DNA of apoptotic cells and nuclei expelled from erythroid precursor cells after macrophages have engulfed them1,2. Here we show that DNase II-/-IFN-IR-/- mice and mice with an induced deletion of the DNase II gene develop a chronic polyarthritis resembling human rheumatoid arthritis. A set of cytokine genes was strongly activated in the affected joints of these mice, and their serum contained high levels of anti-cyclic citrullinated peptide antibody, rheumatoid factor and matrix metalloproteinase-3. Early in the pathogenesis, expression of the gene encoding tumour necrosis factor (TNF)-α was upregulated in the bone marrow, and administration of anti-TNF-α antibody prevented the development of arthritis. These results indicate that if macrophages cannot degrade mammalian DNA from erythroid precursors and apoptotic cells, they produce TNF-α, which activates synovial cells to produce various cytokines, leading to the development of chronic polyarthritis.
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We thank K. Aozasa for pathological analysis of the mice, P. Quartier for critical reading of our manuscript, M. Nishikawa, H. Matsuda, T. Matsuki, A. Seiyama and T. Yanagida for advice and discussion, H. Fukuyama for help at the initial stage of this work, and M. Fujii and M. Harayama for secretarial assistance. This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports, and Culture in Japan.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
Materials and methods are described in detail. (DOC 70 kb)
This file contains text describing Supplementary Figures 1, 2, and 3 (DOC 22 kb)
Targeting vector for the inducible deletion of the DNase II gene. (JPG 293 kb)
Inducible deletion of the DNase II gene. (JPG 108 kb)
No expression of DNase II mRNA in poly(I:C)-treated mice. (JPG 107 kb)
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Kawane, K., Ohtani, M., Miwa, K. et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998–1002 (2006). https://doi.org/10.1038/nature05245
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