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

Kohki Kawane1, Mayumi Ohtani, Keiko Miwa

  • 1Department of Genetics, Osaka University, Osaka 565-0871, Japan.

Nature
|October 27, 2006
PubMed

Insights

Mice lacking DNase II develop chronic polyarthritis due to undegraded DNA. This triggers tumor necrosis factor-alpha (TNF-alpha) production, leading to joint inflammation and rheumatoid arthritis-like symptoms.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Chromosomal DNA degradation is essential during programmed cell death and erythropoiesis.
  • DNase II is a key enzyme responsible for digesting DNA in apoptotic cells and erythroid precursors engulfed by macrophages.

Purpose of the Study:

  • To investigate the role of DNase II in preventing autoimmune diseases.
  • To elucidate the mechanism by which DNase II deficiency leads to chronic polyarthritis.

Main Methods:

  • Generation and analysis of DNase II knockout (DNase II-/-) and conditional knockout mice.
  • Assessment of inflammatory markers, autoantibodies, and cytokine gene expression in affected joints.
  • Evaluation of the therapeutic effect of anti-tumor necrosis factor-alpha (TNF-alpha) antibody treatment.

Main Results:

  • DNase II-/- mice developed chronic polyarthritis with similarities to human rheumatoid arthritis.
  • Activated cytokine genes and elevated levels of anti-cyclic citrullinated peptide antibody, rheumatoid factor, and matrix metalloproteinase-3 were observed in affected joints and serum.
  • Upregulation of TNF-alpha in bone marrow preceded arthritis development, and anti-TNF-alpha antibody administration prevented the condition.

Conclusions:

  • Impaired DNA degradation by macrophages due to DNase II deficiency leads to TNF-alpha production.
  • TNF-alpha activates synovial cells, inducing cytokine production and resulting in chronic polyarthritis.
  • DNase II plays a critical role in preventing autoimmune joint inflammation.

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