Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages

  • An Erratum to this article was published on 01 March 2007

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Arthritis in DNase II -/- IFN-IR -/- and DNase II Δ/- mice.
Figure 2: Inflammatory arthritis in DNase II -/- IFN-IR -/- mice.
Figure 3: Abnormal macrophages.
Figure 4: Protective and therapeutic effect of anti-TNF-α.

References

  1. 1

    Nagata, S. DNA degradation in development and programmed cell death. Annu. Rev. Immunol. 23, 853–875 (2005)

    CAS  Article  Google Scholar 

  2. 2

    Evans, C. J. & Aguilera, R. J. DNase II: genes, enzymes and function. Gene 322, 1–15 (2003)

    CAS  Article  Google Scholar 

  3. 3

    Kawane, K. et al. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science 292, 1546–1549 (2001)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Kawane, K. et al. Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation. Nature Immunol. 4, 138–144 (2003)

    CAS  Article  Google Scholar 

  5. 5

    Yoshida, H., Okabe, Y., Kawane, K., Fukuyama, H. & Nagata, S. Lethal anemia caused by interferon-β produced in mouse embryos carrying undigested DNA. Nature Immunol. 6, 49–56 (2005)

    CAS  Article  Google Scholar 

  6. 6

    Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Feldmann, M., Brennan, F. M. & Maini, R. N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996)

    CAS  Article  Google Scholar 

  8. 8

    Firestein, G. S., Alvaro-Gracia, J. M. & Maki, R. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J. Immunol. 144, 3347–3353 (1990)

    CAS  PubMed  Google Scholar 

  9. 9

    Saxne, T., Palladino, M. A., Heinegard, D., Talal, N. & Wollheim, F. A. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 31, 1041–1045 (1988)

    CAS  Article  Google Scholar 

  10. 10

    Manicourt, D. H., Fujimoto, N., Obata, K. & Thonar, E. J. Levels of circulating collagenase, stromelysin-1, and tissue inhibitor of matrix metalloproteinases 1 in patients with rheumatoid arthritis. Relationship to serum levels of antigenic keratan sulfate and systemic parameters of inflammation. Arthritis Rheum. 38, 1031–1039 (1995)

    CAS  Article  Google Scholar 

  11. 11

    Schellekens, G. A., de Jong, B. A., van den Hoogen, F. H., van de Putte, L. B. & van Venrooij, W. J. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 101, 273–281 (1998)

    CAS  Article  Google Scholar 

  12. 12

    Cohen, P. L. & Eisenberg, R. A. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu. Rev. Immunol. 9, 243–269 (1991)

    CAS  Article  Google Scholar 

  13. 13

    Krieser, R. J. et al. Deoxyribonuclease IIa is required during the phagocytic phase of apoptosis and its loss causes lethality. Cell Death Differ. 9, 956–962 (2002)

    CAS  Article  Google Scholar 

  14. 14

    Okabe, Y., Kawane, K., Akira, S., Taniguchi, T. & Nagata, S. Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation. J. Exp. Med. 202, 1333–1339 (2005)

    CAS  Article  Google Scholar 

  15. 15

    Ramprasad, M. P., Terpstra, V., Kondratenko, N., Quehenberger, O. & Steinberg, D. Cell surface expression of mouse macrosialin and human CD68 and their role as macrophage receptors for oxidized low density lipoprotein. Proc. Natl Acad. Sci. USA 93, 14833–14838 (1996)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Brennan, F. M. et al. Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-alpha (cA2) therapy. Br. J. Rheumatol. 36, 643–650 (1997)

    CAS  Article  Google Scholar 

  17. 17

    Keffer, J. et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991)

    CAS  Article  Google Scholar 

  18. 18

    Feldmann, M. & Maini, R. N. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?. Annu. Rev. Immunol. 19, 163–196 (2001)

    CAS  Article  Google Scholar 

  19. 19

    Feldmann, M. Development of anti-TNF therapy for rheumatoid arthritis. Nature Rev. Immunol. 2, 364–371 (2002)

    CAS  Article  Google Scholar 

  20. 20

    Fujii, I., Shingu, M. & Nobunaga, M. Monocyte activation in early onset rheumatoid arthritis. Ann. Rheum. Dis. 49, 497–503 (1990)

    CAS  Article  Google Scholar 

  21. 21

    Edwards, J. C. & Cambridge, G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nature Rev. Immunol. 6, 394–403 (2006)

    CAS  Article  Google Scholar 

  22. 22

    Bluestone, J. A., St Clair, E. W. & Turka, L. A. CTLA4Ig: bridging the basic immunology with clinical application. Immunity 24, 233–238 (2006)

    CAS  Article  Google Scholar 

  23. 23

    Yokota, S. et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 52, 818–825 (2005)

    CAS  Article  Google Scholar 

  24. 24

    Deng, G. M., Nilsson, I. M., Verdrengh, M., Collins, L. V. & Tarkowski, A. Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nature Med. 5, 702–705 (1999)

    CAS  Article  Google Scholar 

  25. 25

    Collins, L. V., Hajizadeh, S., Holme, E., Jonsson, I. M. & Tarkowski, A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 75, 995–1000 (2004)

    CAS  Article  Google Scholar 

  26. 26

    Leadbetter, E. A. et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Stetson, D. B. & Medzhitov, R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93–103 (2006)

    CAS  Article  Google Scholar 

  28. 28

    Ishii, K. J. et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nature Immunol. 7, 40–48 (2006)

    CAS  Article  Google Scholar 

  29. 29

    Williams-Simons, L. & Westphal, H. EIIaCre—utility of a general deleter strain. Transgenic Res. 8, 53–54 (1999)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Shigekazu Nagata.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Methods

Materials and methods are described in detail. (DOC 70 kb)

Supplementary Figure Legends

This file contains text describing Supplementary Figures 1, 2, and 3 (DOC 22 kb)

Supplementary Figure 1

Targeting vector for the inducible deletion of the DNase II gene. (JPG 293 kb)

Supplementary Figure 2

Inducible deletion of the DNase II gene. (JPG 108 kb)

Supplementary Figure 3

No expression of DNase II mRNA in poly(I:C)-treated mice. (JPG 107 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.